Ontario saw nine times more emergency department (ED) visits per month for cannabis poisonings in young children under the age of 10 after Canada legalized recreational cannabis, according to a study published in JAMA Network Open.
“We saw more frequent and severe ED visits due to cannabis poisoning in children under 10 following the legalization of cannabis, and the legalization of edible cannabis products appears to be a key factor,” said lead author Dr. Daniel Myran, a family physician, public health and preventive medicine specialist, and postdoctoral fellow at The Ottawa Hospital and the University of Ottawa Department of Family Medicine.
The research team looked at all ED visits in Ontario during three periods; pre-legalization, after flower-based cannabis products and oils were legalized in October 2018, and after commercial cannabis edibles (e.g. gummies and chocolates) and other products were legalized and became available for sale in late January 2020.
While there were no deaths, 171 (32.7%) visits required hospitalization and 19 visits (3.6%) required intensive care unit (ICU) admission. ED visits for cannabis poisonings increased the most after commercial edibles were legalized, and more of these visits required hospitalization compared to the other two periods (39% compared to 25%).
Study results:
Pre-legalization (January 2016-September 2018)
- Total ED visits: 81
- Average number of ED visits per month: 2.5
- Percentage of ED visits that were hospitalized: 25%
Legalization of cannabis flower, seed and oil (October 2018-January 2020)
- Total ED visits: 124
- Average number of ED visits per month: 7.8
- Increase in average monthly ED visits compared to pre-legalization: 3 times
- Percentage of ED visits that were hospitalized: 24%
Legalization of edibles and other products (February 2020-March 2021)
- Total ED visits: 317
- Average number of ED visits per month: 22.6
- Increase in average monthly ED visits compared to pre-legalization: 9 times
- Percentage of ED visits that were hospitalized: 39%
“Canada’s approach to legalization was intended to prevent increases in child cannabis poisonings through policies limiting the strength of cannabis edibles, requiring child resistant packaging and education for parents and caregivers.” said Dr. Myran. “Unfortunately, the rates we saw in our study suggest the approach has not met that goal.”
“As more places around the world consider legalizing recreational cannabis, we need to learn how to better protect children from cannabis poisoning,” said Dr. Myran. “More education is a start, but we may need to consider other measures to reduce cannabis edibles’ appeal to young children, such as much stricter limits on what edibles can look and taste like after they are removed from their packaging.”
Researchers at ICES, Bruyère Research Institute, the Canadian Centre on Substance Use and Addiction and The Hospital For Sick Children (SickKids) also contributed to this study.
Cannabis Poisoning
Cannabinoid use as analgesics, antiemetics, appetite stimulants, and anti-spastics are already approved by regulatory bodies such as the US FDA, Health Canada, and the European Medicines Agency. However, several undesired effects may be associated with cannabis and synthetic cannabinoid (SC) use, such as psychosis and self-harm. Exposure to high concentrations of THC could lead to psychological and neurological events, such as dizziness, drowsiness, ataxia, seizures, hypotonia, stupor, coma, and ocular features such as mydriasis and conjunctival hyperemia, in addition to gastrointestinal disorders, and cardiovascular features such as tachycardia, arterial hypertension, and postural hypotension [105,106,107,108,109,110,111,112,113].
However, the use of SCs can lead to more toxic side effects, which may be attributed to the low or no CBD content that has a protective role (anxiolytic and antipsychotic properties), and/or to the high affinity to CB1 receptors compared to THC. The use of SCs is associated with typical acute adverse effect (ex. euphoria, delusions, anxiety, panic attacks, vomiting, seizures, dizziness and others), cardiovascular side effects (tachycardia and hypertension), and long-term adverse effects (high abuse, dependence and tolerance) [111,113].
On the other hand, recreational use of cannabis is considered of low harm, but at the same time may cause damage to the physical and mental health of users in short- and long-term use. Several studies showed that medical cannabis users employed it for recreational reasons, and this may result in intolerable psychoactive effects in patients with no recreational experience, leading them to discontinue medical use [114,115].
Smoking dried cannabis leaves is the preferred consumption method for recreational use because it affords high bioavailability and easy preparation and dosing. Most users experience relaxation, mild euphoria, time distortion with little dysphoria, and anxiety effects, which can increase with the amplification of the THC content, especially in naive users [116].
Cannabis intoxication is dose-related, and its absorbance depends on the route of administration and concentration being used. Inhaled doses of 2–3 mg and ingested doses of 5–20 mg of THC can affect memory and cause short-term memory impairment and loss of attention, while inhaled doses more than 7.5 mg/m2 in adults and oral doses of 5–300 mg in pediatric subjects can cause more serious effects, such as respiratory depression, panic, anxiety, hypotension, myoclonic jerking and other symptoms [117].
The LD50 (the lethal dose at which 50% of the sample population dies) of THC is not determined in humans due to ethical reasons, but in animals it ranges from 40 to 130 mg/kg intravenously. The LD50 of THC inhalation from smoked cannabis in Fisher rats is 42 mg/Kg, a value that is similar to the IV vascular access port value, which indicates that THC is the active intoxicant of smoked cannabis [117,118].
Cannabis-induced adverse effects may be influenced by other several factors such as genetic variation, age, sex, ethnicity, and duration and frequency of cannabis use [119,120,121]. Significant toxicity from cannabis and cannabinoid-containing substances is uncommon in adults, unlike children, who may develop significant symptoms. Fortunately, these toxicity symptoms are usually short-lived and last for several hours [122,123].
A case of cannabis poisoning was reported in a preschool child who was on oral hemp seed oil for three weeks after medical prescription to strengthen his immune system. The child exhibited acute neurological symptoms such as stupor and low reactivity to stimulation, associated with conjunctival hyperemia. THC was detected in the product ingested by the child, and the acid metabolite of THC was detected in the child’s urine [124]. Carstairs et al. reported a case of a 14-month-old child who ingested hashish and was in a prolonged coma for more than 48 hours. The THC metabolite, 11-nor-carboxy-Δ9–THC, was detected in high levels in the patient’s urine, and the patient’s clinical improvement coincided with the decline of the THC metabolite’s level in urine [125].
Generally, cannabis has modest harm that can be avoidable if the starting dose is low, and dose titration is slow. Medical use of cannabis may be associated with adverse events, like drowsiness, fatigue, dizziness, dry mouth, anxiety, nausea, cognitive effects, euphoria, blurred vision, headache, and orthostatic hypotension. Smoking medical cannabis is commonly associated with coughing, phlegm, and bronchitis [126,127,128]. Recreational use is done with no calculated doses nor medical monitoring, likely to be heavy and sustained, and is done most commonly by harmful methods like smoking. Hence, recreational cannabis users are more prone to cannabis poisoning and toxicity. The following discusses harm related to nonmedical cannabis use.
Cannabis’ Effects on the Cardiovascular System
Cannabinoids’ psychological and physiological side effects are well reported, but there is little awareness about the potential cardiovascular effects that are associated with cannabis use. Cannabis can induce higher heart rates, blood pressure, venous carboxy-hemoglobin levels, and can trigger arrhythmias and myocardial infarctions [129].
Cannabinoids’ impact on cardiac function is hypothesized to be a result of stimulation of CB1 receptors. The CB1 receptors are present in the heart, and their stimulation can lead to acute tachycardia and bradycardia, hypotension, decreased cardiac contractility chronically, and elevated oxidative stress [130,131].
Cannabis causes systemic vasodilation, orthostatic hypotension, and an acute dose-dependent increase in the heart rate as well. Some of these effects are mediated by the autonomic nervous system [132]. A study by Wagner et al. found that endocannabinoids can mediate hypotension in experimental models of myocardial infarction [133], similarly to that observed with the use of exogenous cannabinoids. Generally, cannabis-induced cardiovascular symptoms are well tolerated in most young healthy people, but this is not the same for patients with established coronary or atherosclerotic diseases [132,134].
Bachs and Mørland [135] reported six cases of sudden death in males aged 17–43 years old possibly related to cannabis ingestion. Five cases had no previous heart disease, with a record of illicit drug use in just two cases. The sixth case had a previous coronary heart condition and was using heart medications. In all cases, the probable cause of death was an acute cardiovascular event and the presence of cannabis alone was detected in the blood analyses, indicating recent cannabis intake.
Reports have shown that the deceased individuals seemed to be occasional cannabis users and not heavy drug addicts.
Cannabis exposure can increase the risk of myocardial infarction five-fold in the hour after smoking and declined rapidly after the initial hour [136], in addition, it can cause a long-term impact among patients with pre-existing coronary heart disease. One very large study was conducted in the United States to assess the association of recreational marijuana use with the incidence of acute myocardial infarction.
The study involved 2,451,933 patients with acute myocardial infarction aged 11–70 years old from 2010 to 2014. The study found that the lifetime myocardial infarction (ACI) odds were increased by up to 8% in cannabis users. However, the overall odds of marijuana-related mortality were not significantly increased in recreational users presenting with acute myocardial infarction [137,138].
A large study was conducted on 1913 myocardial infarction survivors in United States hospitals. The study found that cannabis use is associated with an increased risk of mortality in individuals with coronary heart disease; cannabis use was associated with a three-fold greater mortality after AMI. The increase in risk was graded with more frequent use, with adjusted hazard ratios of 2.5 for less than weekly use and 4.2 for weekly use [134].
A similar study was performed including 3886 survivors of myocardial infarction followed up for 18 years; the study found an apparent increased mortality rate of patients presenting with acute MI who were cannabis users, but the increase did not reach nominal statistical significance [139].
Recently, cannabis use is implicated as a risk factor for Takotsubo cardiomyopathy, characterized by transient left ventricular wall apical ballooning that leads to temporary left ventricular dysfunction. Nogi et al. reported a mid-ventricular variant takotsubo cardiomyopathy case associated with cannabinoid hyperemesis syndrome (recurrent episodes of severe nausea and vomiting, and colicky abdominal pain associated with long-term, heavy cannabis use) in a long-term marijuana user [140]. Khalid et al. reported a case of Takotsubo cardiomyopathy associated with a urine drug screen positive for THC [141].
A study performed by Alliu et al. to investigate the association of cannabis and Takotsubo cardiomyopathy concluded that there is a significant association between non-dependent cannabis use and increased odds of Takotsubo cardiomyopathy [142].
There are two reports of teenage boys diagnosed with cannabis-induced myocarditis [143,144]. One of them is a 16-year-old teenager who was diagnosed with acute left heart failure secondary to acute myocarditis due to cannabis abuse. The patient required support by a left ventricular assist device for 96 days until his cardiac function was fully recovered [144]. A case of pediatric death after exposure to cannabis was reported in 2017. The death was secondary to myocarditis in an 11-month-old male who was confirmed to be exposed to cannabis. The patient suffered from a seizure which was followed by CNS depression, and developed cardiac arrest and consequently has died [145]. Based on these cases, it is recommended to include cannabis exposure in the differential diagnosis of young patients presenting with myocarditis [143,145,146].
Cognitive, Psychiatric, and Psychomotor Effects
Activation of the CB1 receptor can lead to central side effects, such as ataxia and catalepsy [147]. Binding of THC to CB1 receptors can affect perception, memory, and movement, as a result of selective adenylate cyclase activity inhibition consequent to CB1 activation, and may cause dysphoria and psychotomimetic effects.
Cannabis use is linked to cognitive impairment; short-term memory impairment is a well-established effect of acute cannabis intoxication [148]. The memory impairment after cannabis use is thought to be attributed to THC’s effect on hippocampal CB1 receptors; the hippocampus is a region in the brain implicated in certain forms of learning and memory and is dense with CB1 receptors [149].
THC and CB1 agonists reduce presynaptic neurotransmitter release and consequently disrupt synaptic long-term plasticity in the hippocampus [150]. In a study performed on rodent models, rimonabant (37) (Figure 5), a CB1 receptor antagonist, was administered intrahippocampally followed by systemic administration of THC. It was found that THC’s memory deficits were reversed by rimonabant.
These findings support the notion that hippocampal CB1 receptors mediate the memory deficit effect of THC [151]. Moreover, Marsicano et al. showed that CB1 knockout mice exhibited impaired short- and long-term extinction in tests of auditory fear conditioning, reduced forgetting, unaffected memory acquisition and consolidation on memory tests [152].
Although in comparison with alcohol use, long-term use of cannabis is not associated with severe cognitive impairment [153], memory problems are frequently associated with short and long-term cannabis use, such as subtle memory and attention impairment, as well as impaired ability to integrate and organize complex information.
Cannabis-related cognitive impairment increases with the increased duration of use [112]. A study by Herning et al. found that heavy cannabis users showed a significant increase in cerebrovascular resistance and systolic blood flow velocity compared to control subjects; this increase persisted after a month of monitored abstinence, so the authors suggested that cannabis-related cognitive deficit is partially caused by increased cerebrovascular resistance and decreased blood perfusion to the brain [154].
Other central effects of cannabis include disruption of psychomotor performance, motor function, and reaction time, effects that are proposed to result from the memory lapse. In fact, acute administration of cannabis is associated with an initial stage of excitement and psychomotor agitation, followed by a state of dysarthria, ataxia, physical inertia, and general incoordination [112].
The psychomotor impairment effect of cannabis is additive to alcohol’s effect; this has made cannabis a major risk for road accidents [155,156]. Cannabis also is linked to increased interpersonal violence [157], an effect that can be attributable to acute psychomotor agitation. Additionally, a 12-year forensic investigation of deceased illicit drug users found that cannabis use was associated with the most violent suicide and death means, particularly severe motor vehicle accidents [158].
Some research studies showed a positive association between cannabis use and suicide attempts, but other investigations denied this association. Price et al. found that there is no evidence of an association between cannabis use and suicide risk after controlling for many variables such as life circumstances and mental health in childhood and early adolescence [153]. A study by Naji et al. showed that there is not a specific association and observed that the heaviness of cannabis use may have a very modest association with suicide attempts in adults.
On the contrary, the impact of cannabis use can differ in people with psychiatric disorders, there being a significant risk factor for suicide attempts in psychiatric patients, such as unemployed and mood-disturbed people [154]. A new study by Fontanella et al. showed that cannabis use disorder (CUD) increases the risk of self-harm and death from involuntary or voluntary overdose in young people with mood disorders [155]. These findings should serve as information for healthcare professionals and policy makers to support patients with mood or psychiatric disorders.
In general, the most common adverse psychiatric effect of cannabis is anxiety [156,159]. However, several studies showed a relation between cannabis use and the risk of acute toxic psychosis and schizophreniform spectrum disorders [3,160,161,162,163,164,165,166,167]. Low doses of THC (2.5–15mg) can affect memory, motor function, and other acute side effects, while large doses of THC (˃100mg) can produce chronic adverse effect such as delusions, disorientation, visual and auditory hallucinations, paranoid ideations, mania, and schizophreniform psychosis [156,168].
These reactions are usually dose-related and self-limiting, and they can last from a few days to weeks, depending on the potency of the preparation. Cannabis users with a family history of psychotic disorders are particularly vulnerable to the psychotic adverse effects of cannabis. Cannabis was found to precipitate psychosis in people with a family history of psychotic disorders [156]. There is sufficient evidence that the frequent use of cannabis by young people could increase the risk of developing psychotic disorders or having the first episode of psychosis earlier than usual in their life [168,169]. Cannabis also has been found to exacerbate pre-existing mental illness. Furthermore, long-term cannabis use is implicated in other mental disorders such as bipolar disorder [159,170,171,172] and depression [173,174].
Effects on the Respiratory System
Cannabis (marijuana) is the most commonly smoked substance in the world after tobacco. Among the different ways of intaking cannabis, inhalation through the lungs is the most usual intake method, whether by cigarette smoking, pipes, or vaping using special devices. Compared with tobacco smoking, cannabis smoking is usually done with deeper inhalation and greater breath-holding time in order to achieve a higher absorption of THC.
Effects of cannabis smoking on the lungs depend on the depth of inhalation and the duration of breath holding. The pattern of smoking cannabis results in greater deposition of substances with toxic potential in the lungs [175], and the physical dynamics of smoking were even proposed to cause lung disease other than cannabis itself [176]. As for the composition of cannabis smoke, it contains THC, the main psychoactive component, and other substances such as CBN, CBD, and a large mixture of compounds including volatile components such as ammonia, carbon monoxide, hydrocyanic acid, and nitrosamines, and tar components (phenols, naphthalene, benzanthracene, procarcinogenic benzopyrenes) [177]. Many of these compounds are bronchial irritants, mutagens, and carcinogens [178,179].
Chronic smoking of cannabis is associated with bronchitis, emphysema, and squamous metaplasia of the tracheobronchial epithelium. These symptoms are more frequent in cannabis-only smokers than in tobacco-only smokers, and they are even higher in those who smoke both cannabis and tobacco [180]. Other described pulmonary complications of cannabis include lung bullae and cystic lung disease, signs of the destruction of lung tissue, decreased lung density with increased lung volumes, and secondary pneumothorax because of bullous rupture [176,181,182,183,184].
Cannabis smoking is also associated with lung cancer, as the smoke contains a number of potent carcinogenic compounds [185,186,187,188,189]. Low doses of THC were found to accelerate the proliferation of lung carcinoma cells in vivo [190]. Moreover, several case reports have suggested a link between cannabis smoking and aero digestive tract (mouth, tongue, esophagus) cancer [179].
For further understanding the relationship between cannabis smoking and pulmonary function, Tetrault et al. conducted a systematic review of the literature and selected 34 relevant publications examining short-term and long-term cannabis smoking and pulmonary function and respiratory complications. The study concluded that short-term cannabis smoking is associated with acute bronchodilation. In fact, for many years, marijuana was used as an alternative medicine to treat asthma symptoms due to its mild bronchodilation. while in the longer term, cannabis smoking is associated with increased respiratory symptoms of coughing, phlegm, and wheezing, suggestive of obstructive lung disease [191].
These findings were supported by the conclusion of a systemic review and meta-analysis of 22 studies, in which low-quality evidence that associates cannabis smoking with coughing, sputum production, and wheezing was found [192]. Additionally, a patient-centered observational study was conducted on 8932 patients with cannabis use, or at least two cannabis positive urine drug screens, and matched with non-cannabis-using patients; the results show that cannabis use was associated with a higher risk for pneumonia, asthma, and COPD, regardless of tobacco use disorder state [193]. Some in vitro and animal studies have suggested that cannabis results in impaired bactericidal activity of lung alveolar macrophages and consequently a depression of the intrapulmonary antibacterial defense systems [194,195]. Despite that, there is no clear evidence that cannabis smoke causes significant immunological damage in humans.
Effects on the Hormonal System and Fertility
Men and women of reproductive age are the most prevalent users of cannabis, and thus cannabis’ impact on the fertility and reproduction system is of special importance. Cannabinoids, including THC, were found to exert anti-androgenic effect by binding to androgen receptors and acting on the hypothalamus-pituitary-adrenal (HPA) axis [196].
Animal studies have shown that cannabis influences several endocrine processes affecting sexual hormones as well as other hormones like melatonin and growth hormone [196,197,198]. It was demonstrated by animal models that cannabis is related to testicular atrophy, reduced libido, and sexual function [196,199]. However, until now, such effects have not been observed in human studies [199].
Cannabinoid receptors are expressed in human sperm [200]; this suggests that sperm can be directly affected by alterations in the endocannabinoid balance. Research in male humans found evidence that cannabis has a role in reducing sperm count and concentration, decreasing sperm motility and viability, inducing abnormalities in sperm morphology, and inhibiting fertilizing capacity [194,201].
In addition, another research study demonstrated changes in sexual hormones upon using cannabis. While cannabis’ effect on testosterone levels is largely undetermined, luteinizing hormone (LH) levels appear to be lowered and levels of the follicle-stimulating hormone are unchanged (except in heavy chronic use cases) [199]. The role of follicle-stimulating hormone (FSH) is known in supporting developing spermatozoa by stimulating Sertoli cells, while LH stimulates testosterone production from Leydig cells [202]; lowered levels of FSH and LH by THC can cause reduced testosterone production by the Leydig cells [203]. Moreover, chronic cannabis use may increase prolactin concentrations in men, which may lead to gynecomastia [204].
Cannabis’ effect on female reproduction has not been fully studied. A study was conducted by Somenath Ghosh on female mice which were given different concentrations of cannabis extract orally by micro-pipette to study the effect of canna-bis on female reproductive system. The results show that chronic cannabis exposure induced oxidative stress and impairment in the female mouse reproductive system which is characterized by a significant decrease in ovarian and uterine weight [205].
Another study was conducted on healthy adult females and the results show that cannabis smoking causes an acute decrease in prolactin concentrations, but prolonged use may increase the hormone concentrations, leading to galactorrhea [204]. Cannabis can reduce estrogen and progesterone production by disrupting the hypothalamic release of gonadotropin-releasing hormone (GnRH), which may lead to an ovulatory menstrual cycle and reduced female fertility [205].
Cannabis inhalation during the luteal phase of the menstrual cycle may result in transient suppression of levels of prolactin and LH [206]. Nevertheless, there is no conclusive evidence of cannabis’ effect on menstruation or on levels of estrogens, progesterone, testosterone, prolactin, LH, or FSH in women [207,208].
In general, cannabis-related endocrine changes may not be significant in adults, but they may be of high importance in prepubescent males and females, in whom cannabis may suppress sexual maturation [204,209]. Several animal studies showed that cannabis (specifically exposure to THC) can lead to pubertal delay and affect pubertal maturation [210]. However, evidence in humans is limited except for a case of a 16-year-old youth who showed delayed puberty and low testosterone levels with heavy cannabis smoking, and after discontinuation of cannabis smoking, his testosterone levels increased and pubertal development advanced [211]. Hence, an urgent understanding of the effect of cannabis on pubertal timing and tempo in children is needed. A systematic review was conducted to evaluate the effects of cannabis use on puberty in humans. The results show that there are no existing articles that relate cannabis use with the delay in puberty in children and highlight the importance of this issue for future investigation [210].
Maternal Cannabis Exposure and Infant Outcome
Cannabis use among pregnant women is frequent. International studies estimated that 4.5–7% of all pregnancies are exposed to cannabis [212,213,214], and cannabis was the most common illegal drug among pregnant women in western countries [214,215,216]. Evaluation of maternal cannabis use’s effects on fetal and infant outcomes is difficult, as cannabis use is not always reported, and cannabis is usually consumed with other drugs, especially alcohol, tobacco, and caffeine.
THC and other cannabinoids cross the placenta rapidly and enter the embryo [217,218], and they are secreted in breast milk. There is no evidence of fetal malformations, but accumulating evidence from human and animal studies indicates that maternal cannabis use during pregnancy can alter fetal development and infant outcomes. Chronic maternal cannabis use is associated with reduced weight gain and low body weight at birth, which is the most noticed effect related to maternal cannabis exposure. Roncero et al. [213] conducted a systemic review of the literature on cannabis use during pregnancy and fetal outcomes, and they found that maternal cannabis use may be associated with developmental abnormalities in general, development of mental disorders such as depression and attention deficit hyperactivity disorder (ADHD), and changes in brain chemistry, which was observed in both humans and animals [213].
Many developmental defects related to prenatal cannabis exposure were identified by human longitudinal studies of in utero cannabis-exposed offspring. Defects in cognition, executive functioning, and visuospatial working memory, and lower school-age intellectual development were identified to be related to in utero cannabis exposure. In utero exposure to cannabis was associated with deficits in tasks requiring visual memory, analysis, and integration and with impulse control in tasks requiring sustained attention [219,220,221,222,223]. Cross-sectional retrospective studies have linked maternal cannabis use to impaired memory, impulse control, quantitative reasoning, problem-solving, and verbal development in children aged 1–11 years old [224], as well as alterations in emotional reactivity, neurobehavioral performance, neurophysiological integrity, increased tremors and startlings in infants [225,226,227].
A 17-year period study was conducted on infants and fetuses with birth defects to investigate the relation between cannabis use during pregnancy and birth defects. Investigation showed that birth defects associated with prenatal cannabis use affect the cardiovascular system, the gastrointestinal system, and the central nervous system [228]. In addition, a retrospective case-control study of 204 pairs found an 11-fold risk of developing non-lymphoblastic leukemia in the offspring of mothers who had been exposed to marijuana within a year before pregnancy or during pregnancy [229].
Huizink presented an overview of studies on prenatal cannabis exposure in humans in which findings on fetal development, birth outcomes, neonatal and infant behavior, and cognitive development were discussed. It was concluded that there is evidence that fetal development is affected by maternal cannabis use during pregnancy, while evidence is inconsistent on the effects on infant behavior and cognition [230].
Studies on animal models of prenatal cannabis exposure have supported the findings of altered cognitive, emotional, social, and motor aspects in offspring [231,232,233]. Rodents prenatally exposed to isolated THC or WIN 55,212-2 (a CB1 receptor agonist) have shown lasting changes in epigenetic regulation, synaptic plasticity, and dopamine neuron signaling [234,235,236,237]. However, synthetic cannabinoid or THC injections cannot be considered a good representative of whole-plant cannabis, which contains a large number of pharmacologically unique phytocannabinoids [12,238].
A recent study was conducted to assess the neurodevelopmental effects of maternal cannabis vapor exposure on offspring of rats by administering whole-plant cannabis extract vapor. In this study, a new approach of mimicking the intrapulmonary administration route was applied taking advantage of ‘e-cigarette’ technology to deliver vaporized extracts of whole-plant cannabis, to attain relevant concentrations in plasma and brain tissue. The study found that prenatal cannabis vapor exposure resulted in long-lasting effects on the behavioral profile that extend into adulthood, and the effects indicated an increase in emotional reactivity, alterations in social play behavior, and behavioral flexibility [239].
Cannabis use among pregnant women is not extensively researched. Additional research is needed to detect and better understand the effects of maternal cannabis use on fetal development and offspring. Early detection, alerting, and education of women in childbearing years on the effects of cannabis use during pregnancy is necessary to minimize possible harm. Moreover, it is also important for healthcare professionals to have good scientific knowledge and to be well trained in this field.
Cannabis-Tolerance and Dependence
Increasing cannabis use due to growing legalization in different countries world-wide led to the development of cannabinoid abuse disorders and adverse effects [240]. Cannabis use disorder is defined according to the Diagnostic and Statistical Manual of Mental Disorders (DSM–5) as a pathological problematic pattern that leads to control and social impairment, physiological adaptation, and tolerance [241,242].
Long-term and heavy chronic use of cannabinoids can cause addiction, especially when started in adolescence, and tolerance, which results in physical dependence that leads to withdrawal syndrome when stopping drug use [240]. Cannabis withdrawal symptoms can start after 1 or 2 days of cessation and last for one to two weeks, and the symptoms include irritability, depression, decreased appetite, anger, and difficulty sleeping, which is similar to tobacco withdrawal syndrome [242,243].
These symptoms may vary among individuals and depends on the amount and potency of cannabis use prior to cessation; usually mild to moderate symptoms are treated in an outpatient detoxification setting, but severe symptoms need inpatient care [244]. Different approaches are now considered for the treatment of cannabis withdrawal symptoms. Recently, cannabidiol was considered as a potential treatment for cannabis withdrawal symptoms due to its safety and tolerability with few side effects and broad range of pharmacological effects that include the inhibition of hydrolysis and reuptake of endocannabinoids, in addition to its ability to interact with the effects of THC.
A phase 2a trial was conducted to determine the efficacious and safe doses of cannabidiol, which were 400 and 800 mg, to reduce cannabis use [245]. Nicotin patches (NP) at 7 mg dose were also studied for their potential to reduce withdrawal symptoms in cannabis-dependent individuals who are not heavy users or not nicotine dependent, and the results showed that NP has the ability to reduce withdrawal negative effect in individuals with cannabis use disorder [246].
Moreover, exogenous progesterone was suggested as a therapy in women who suffer acute cannabis withdrawal symptoms due to its noticed effect in reducing cannabis craving. Large size and longer duration studies are needed to support the role of exogenous progesterone in the assessment of cannabis withdrawal symptoms [247]. The effects of other drugs on reducing cannabis withdrawal symptoms were also investigated, such as nabiximols, nefazodone, lofexidine, and oral THC; the results show their ability in the reduction in anxiety, sleep disorders, craving, and depressed mood, but they were associated with negative side effects that worsen withdrawal symptoms, such as irritability [248,249]. More studies need to be conducted in order to better understand cannabis dependence. Until now, there are no approved drugs for the treatment of cannabis dependence, and psychotherapeutic techniques are the main therapy [250].
Cannabinoids Drug Interactions
Cannabinoids such as THC, CBD, and CBN are extensively metabolized by cytochrome P450 in the liver and intestines. THC and CBN biotransformation occurs mainly due to CYP2C9 and CYP3A4, while CBD biotransformation occurs due to CYP3A4, and may undergo direct conjugation via UDP-glucuronosyltransferase (UGT) enzymes. Several drugs can affect cannabinoid metabolism, and at the same time, cannabinoids can affect the metabolism of other drugs [251,252]. CYP3A4 inhibitors such as ketoconazole, macrolide, verapamil, and augmentin can increase THC and CBD concentrations to double [253].
CYP2C9 inhibitors such as cotrimoxazole, fluoxetine and amiodarone can also increase THC concentration and its psychoactive effects. On the other hand, CBD inhibits CYP2C19 and can increase the level of clobazam to threefold, increase bleeding when combined with warfarin, and increase tacrolimus levels by three-fold by inhibiting CYP3A4/5 [254,255]. Additive effects can also occur when combining cannabis with other drugs such as (i) sympathomimetics, which can result in tachycardia, hypotension and hypertension; (ii) CNS depressants, e.g., alcohol, or muscle relaxants and opioids, provoking drowsiness and ataxia; and (iii) anticholinergic, which cause tachycardia and confusion [253,254]. In the case of smoked cannabis, drug clearance can be increased with regular cannabis use, i.e., more than two cigarettes per week. Smoked cannabis increases the clearance of several drugs metabolized by CYP1A2 such as theophylline, which can be increased to 40% in addition to clozapine and olanzapine [248,253].
reference link : https://www.mdpi.com/2072-6651/13/2/117/htm
More information: Unintentional Pediatric Cannabis Exposures Following Legalization of Recreational Cannabis in Canada, JAMA Network Open (2022). DOI: 10.1001/jamanetworkopen.2021.42521
If your child has accidentally consumed cannabis, contact the Ontario Poison Control Centre at 1-800-268-9017. Cannabis poisoning in babies, children and youth is a medical emergency. Call 9-1-1 if your child is ill and/or has difficulty breathing. Caregivers can prevent poisonings by keeping cannabis products in a locked container away from other food and drinks, and out of children’s reach. Learn more about the risks of cannabis and how to prevent unintentional poisoning.
