Pediatric Brain on Cannabinoids: Adverse Effects of Cannabinoid Products in Children and Adolescents

Abstract

Cannabinoids (phytocannabinoids and synthetic cannabinoids) are most often used during adolescence and given the changing norms, enhanced potency, reduced societal perceptions of risk and multitude forms of products for consumption, clinicians need to be become more cognizant of cannabinoid products and their effects. The aim of this narrative review is to briefly discuss acute toxicities and a few chronic toxicities associated with cannabinoids that clinicians are likely to treat. In addition, cannabinoid toxicokinetics and toxicodynamics as it pertains to the clinical effects will be discussed as well as the route of exposure and the clinical implications for therapeutics. Although the neurodevelopmental effects of naturally occurring endocannabinoids will be briefly mentioned, it is beyond the scope of this review to discuss in detail. Regardless, clinicians, parents and patients should be aware of the potential implications that exogenous cannabinoids (cannabis) may have in altering the normative trajectory of brain maturation in pediatric patients.

1. Introduction

Cannabis (Cannabis sativa) has been widely studied and is used for recreational, medicinal and in scientific research with its principle bioactive components being cannabinoids. The term “Cannabis” is actually the genus of the flowering plant whose well known species include sativia, indica, and ruderalis. When the cannabis flower bud/leaves are dried, it is referred to as marijuana [1] as long as the plant contains more than 0.3% of THC, otherwise it is referred to as hemp. Cannabis is comprised of over 100 different cannabinoids and non-cannabinoid substances and is a complex psychoactive plant that contains many cannabinoid components of unclear effects and they have commonly been neglected [2]. The four most abundant cannabinoids are Delta-9 tetrahydrocannabinol (Delta-9 THC, or THC), cannabinol (CBN), cannabidiol (CBD), and cannabigerol (CBG) [3]. The abuse related potential of cannabis is mediated by THC, the main phytocannabinoid component thought to be responsible for the majority of the psychoactive, mood altering and reinforcing properties of cannabis.

Sativia variety has the highest percentage of THC with indica and ruderalis varieties have the higher percentages of CBD [4]. It is the ratio of THC/CBD that defines potency and its psychoactive effects. Of course, there are hybrid varieties making it even more difficult to know what the THC/CBD ratio is, and consequently the potency. Higher potency is associated with euphoric, anxiolytic and relaxing effects while lower potency is usually more sedating and similar to medical cannabis. Through the years there has been global increases in THC levels and decreases in CBD levels and both (increases in THC potency and decreases in CBD) have been implicated in causing health complications from cannabis use [5]. CBD is non intoxicating and appears to minimize some harmful effects of THC including memory impairment and psychotic symptoms. As a result, evidence appears to indicate that the potency of THC and CBD and their relative ratios are important factors in determining the level of harm an individual may experience [6].

Based on the etiology of the cannabinoids, they are generally separated into three groups: endocannabinoids, phytocannabinoids and synthetic cannabinoids. Endocannabinoids (eCB) are endogenously produced in the human body and are lipid ligands that interact with at least two “G-protein” coupled receptors (CB1 and CB2) located in the brain and peripheral nervous system. The activation of these receptors causes an inhibition of the release of neurotransmitters (acetylcholine and glutamate) and indirectly effecting many other receptors. The CB1 and CB2 receptors are located presynaptically which means that cannabinoids modulate neurotransmitter release [7]. The concern during prenatal and post birth development through the adolescent years is that exogenous cannabinoids may alter the neurodevelopment of the brain since evidence points to CB1 receptors being more prevalent during developing years than in the adult [8]. Phytocannabinoids are naturally occurring cannabinoids found in the cannabis plant with the four most abundant cannabinoids already mentioned above. Finally, synthetic cannabinoids (SCs) are human-made (chemically engineered) mind altering chemical agonists that structurally may or may not be similar to naturally occurring phytocannabinoids but are full agonists at cannabinoid receptors, unlike THC which is a partial agonist of CB1 and CB2 receptors [9]. It is the CB1 receptor and its interaction with THC or similar ligands such as SCs that leads to the psychotropic effects. Through antagonistic effects on the CB1 receptor, marijuana induces its mental and behavioral effects. The initial research into biologically active analogs (essentially SCs) were performed by pharmaceutical companies pursuing biological activity but lacking psychoactive side effects. At present, there are two SCs derived from cannabis that are used medically and regulated and those are dronabinol and nabilone [10]. Dronabinol is a scheduled III drug and Nabilone is a schedule II drug with the former used for nausea and vomiting related to chemotherapy, anorexia or AIDS, and the latter is also used for nausea or vomiting from chemotherapy. Unfortunately, underground laboratories have utilized this research and produced illicit compounds used as alternatives for marijuana. The physiology of the human endocannabinoid system makes it possible to be exploited and makes it receptive to exogenous synthetic compounds, making it an easy target for abuse [11].

2. Endocannabinoid system

The endocannabinoid system consists of the endocannabinoids and the cannabinoid receptors. Cannabinoid receptors (CB1) are expressed in the brain, peripheral nervous system and peripheral tissues such as the heart, gut, liver, reproductive system, immune system and the respiratory system [12]. CB2 subtype is expressed in peripheral organs with immune function such as spleen, thymus, tonsils, and in cells such as macrophages and leukocytes. Despite what is known about cannabinoid receptors, what is still subject to debate is the physiologic function of these receptors. Of importance however, is that CB1 receptors are the most prevalent G-protein coupled receptors in the human brain and is highly expressed in cognitive processing regions and in the reward regions of the brain [13]. CB1 and CB2 receptors play a key part in a yet to be fully understood endogenous cannabinoid signaling system. The principal lipid ligands known as anandamide (AEA) and 2-arachidonyl glycerol (2-AG) are responsible for signal transduction but may also themselves be acted upon by specific and important enzymes during signal transduction. Although the components of the endocannabinoid system may remain consistent through life, its function is drastically different during nervous system development as eCB play important roles in neurodevelopment and synaptic plasticity [14, 15]. Unfortunately, it is also under appreciated that brain development does not stop until late adolescence (18–24 years old) [16].

In the brain, the endocannabinoid system is involved in sleep regulation, anxiety control, reward reaction, appetite control, neuroprotection and neural development. During adolescence, eCB and their respective receptors play a vital role in neurodevelopment processes such as pruning and synaptic plasticity [17, 18]. During fetal growth and development and during continued maturation post birth, eCB play an important role in central nervous system (CNS) development with neuro progenitor cells which are multipotent stem cells that can form new cells in the nervous system. So eCB system plays a critical regulatory role throughout development, from the determination of cell fate determined by progenitor cells and neuronal migration to regulation of synaptic transmission and signaling pathways of the fully developed CNS [19]. The precise mechanism by which eCB system molds adolescent brain development however is not clear.

2.1 Psychiatric implications of exogenous THC on the endocannabinoid system

What is clear, however, is that cannabis use is commonly initiated during adolescence and that the exogenous THC psychotropic impact is experienced through the developing eCB system during a vulnerable period of neurodevelopment. One of the concerns, during this neurodevelopment transition period is that marijuana will “over activate” the eCB system resulting in behavioral abnormalities and possibly addiction [7, 20]. Adolescence is a critical time period for brain development which involves the eCB system and there is some evidence noted below that would indicate that this age group’s mental health may be particularly vulnerable to the effects of exogenous THC. Some of the behavioral abnormalities that have been linked to cannabis use in younger people, before the age of 17, are schizophrenia, psychosis, bipolar disorders and addiction [15]. More specifically, Goggi and coworkers found that there was an association of cannabis use during adolescence (age < 18 years) and depression, suicidal ideation and suicide attempts [21]. The authors’ meta-analysis suggest that cannabis could be a significant factor, among many, contributing to depression in young adulthood and is consistent with the negative influence of cannabis in brain plasticity during development.

Adolescent impulsivity associated with prolonged myelination process and the lack of prefrontal inhibitory control during this period of growth and development could set this population up for some mental health issues precipitated by cannabis. Kristen Schmidt and colleagues [22], in their systematic review of adolescent cannabis use and suicide, found there to be a significant relationship among suicidal thoughts, behavior and suicide attempts with adolescent cannabis users. The UCLA psychiatric group suggests that cannabis is an independent predictor of suicide in this age group and that frequency of cannabis use is associated with increased suicide attempts. Consistent with this finding in adolescents was the study by Hosseini and Oremus from Canada showing earlier age-of-initiation of cannabis use was associated with a higher risk of psychosis [23]. Indeed, early-onset cannabis use (age < 18) but not late onset cannabis use was associated with a higher risk for major depressive disorder by Schoeler and colleagues out of London, especially for individuals with higher frequency cannabis use [24]. Although the causality of cannabis use and mental health issues remain unclear among adolescent studies [25], there are other issues that are also important for clinicians to counsel adolescents and parents regarding cannabis use: cannabis may have detrimental effects on cognition, brain and educational outcomes that can persist beyond acute intoxication and second, improvement of these detrimental effects appear possible with sustained abstinence [26].

2.2 Cannabis use disorder and cannabis withdrawal syndrome

The most frequent negative effect of chronic cannabis exposure is addiction and regular cannabis users may develop a cannabis use disorder called CUD. CUD is defined as the inability to stop consuming cannabis even when it is causing physical or psychological harm, generally including compulsive use and neglect of obligations [27]. In many regular cannabis users, cannabis withdrawal syndrome (CWS) may occur with cessation of cannabis use and is an indicator of CUD. Signs and symptoms of CWS include cravings, irritability, sleep disruption, aggression, weight loss, depression, anxiety, sweating, headaches, tremors and fatigue and may occur within days of stopping cannabis [15]. There are no approved medications for either CUD or CWS. However, initial treatment would be similar to many other withdrawal syndromes. Supportive care and treatment for CWS for those with no prior psychiatric history, has included a tapering dose of phenobarbital (seizures), Escitalopram and low dose benzodiazepines (anxiety), clonidine, (generalized withdrawal symptoms), Naltrexone (cravings), and Metoclopramide (nausea) [28].

Although the temperament of the above information may imply some form of consensus that regular cannabis use during adolescence has uniformly negative consequences for cognitive impairment, the evidence is very complex and evolving and will likely take years to elucidate. For adolescents or young adults who come in for cannabis related toxicity and appear to be “regular or heavy users”, the clinician may want to offer advice regarding the potential for adverse cognitive, neural, and educational effects from daily cannabis use [26]. There is some evidence, however, for cognitive recovery after 4–6 weeks of abstinence from cannabis use [29], although there may be some folly in that recommendation to quit as many adolescences and adults who are regular users find it difficult to end their cannabis addiction because of possible neuroadaptation that may occur with regular use [30, 31]. Current evidence would suggest that initiation of cannabis use should be delayed until much later in adolescence, use should be occasional and not daily, high potency marijuana should be low, and use occurs in ways other than smoking [32].

3. Cannabis consumption

THC is the primary psychoactive chemical in cannabis that is responsible for producing the subjective “high”, feelings of euphoria, as well as the adverse effects caused by overdosing such as panic, anxiety, paranoia, and psychosis [33, 34]. The somatic or physiologic effects such as changes in heart rate (HR) and Blood pressure (BP) along with increased cardiac output, cardiac workload, and consequently oxygen workload are also an effect of THC [35]. CBD (acid metabolite THC-COOH) is non psychotropic.

In 12th graders, cannabis has the lowest rate of abeyance of all substances used by this age group [36]. In 2018, over 1/3 of 12 graders used cannabis with 28% of 10 graders and 11% of 8th graders also admitting to cannabis use to some extent, with prevalence starting to move downward in 2021 [37]. Now the effects of cannabis legalization on availability and diminished perceived risk, especially by 12th graders, may be associated with increased adolescent cannabis use. Complicating the increased use is the enhanced potency of the cannabis flower of today because of specialized cultivation techniques resulting in at least a threefold increase in THC from 4% in 1995 to 12% in 2014 [38] with some cannabis flower strains containing upwards to 30% [39]. The effect of legalization of Cannabis has reduced prices and increased sales of high potency cannabis products such as edibles, oils, extracts, and waxes containing even higher amounts of THC (> 70%) [40]. Although changes are likely coming regarding marijuana, cannabis is classified as a Schedule 1 drug by the United States Drug Enforcement Agency (USDEA) and therefore is not regulated except for dronabinol, nabilone and CBD.

One of the underappreciated effects of decriminalization and legalization of cannabis is the impact it has on both the unintentional and intentional exposure to infants and young children [41, 42]. Widespread use of cannabis simply translates to greater access to children. In contradistinction to numerous neurologic manifestations of cannabis intoxication in adolescents and young adults, such as mood and attention alterations, acute psychosis, ataxia, tremor, nystagmus, excessive motor activity or muscle relaxation, infants and young children may exhibit primarily impaired consciousness or sudden, unexplained acute encephalopathy. If intoxicants such as cannabis are not considered in the differential along with infectious, trauma, and metabolic dysfunction or dysregulation (hypoglycemia) then this necessitates larger and more invasive workups or procedures that otherwise might be obviated if only a urine tox screen was considered. Many times parents may not be forthcoming in providing information because of social or legal concerns for child abuse and many adults consider cannabis to be harmless [43]. A very recent publication comparing pre versus peri-post legalization of cannabis found children presenting to the emergency department peri-post legalization were significantly more likely to have altered mental status and respiratory involvement that required pediatric intensive care admissions. Additional clinical findings include behavioral changes of the child, ataxia, respiratory depression, seizures, apnea and coma [42].

Regarding psychiatric issues and cannabis, research has shown a dose-dependent linking between THC and psychosis although cause and effect has not been established [44]. Acute cannabis use or intravascular THC administered to normal healthy adults produces psychotomimetic effects similar to that seen in chronic psychosis [45]. In adolescents, cannabis use at 15 years of age is associated with greater likelihood of psychosis later in life but remains unclear if early onset cannabis use is an independent predictor of adverse events later in life. Indeed, most adverse events observed in individuals reporting early-onset use involve frequent and or high potency cannabis use as the most relevant factor [32].

There are many different modes of consumption of cannabis and each comes with its own risks and benefits. It behooves the user to understand, and novice users in particular, need to appreciate the differences that route of exposure can have in the initiation of effects, the duration of psychoactive effects or the intensity of the “high” [46, 47].

4. Smoking and vaping (aerosolization)

The main reason most people smoke cannabis is to experience the so-called high, which typically includes relaxation, some euphoria, perceptual alterations including time distortions and enhancing every day experiences such as eating, watching movies, listening to music and engaging in sex [48]. In a social context, the high could be accompanied by infectious laughter, talkativeness which enhances sociability coinciding with the peak effects within 30 minutes and ending in 1–2 hours [49]. Acute adverse effects of cannabis use include anxiety and panic attacks, psychotic symptoms and automobile accidents due to the effects on coordination, alertness, and judgment [49].

Smoking marijuana leaves or cannabis plant material is, by far, the most popular means by which to obtain the desired psychoactive effects. In Colorado, USA, approximately 2 ounces of marijuana is sufficient to make 50 marijuana cigarettes [50]. Compared to other forms of consumption, such as vaporization, ingestion, transcutaneous, rectal or vaginal routes, smoking generates the most efficient, consistent and instantaneous “high” in delivering THC in a dose dependent manner to the brain. Bioavailability by smoking ranges between 10 and 35% depending upon the regularity of smoking, depth of inhalation, breath hold and puff duration [35]. Combustion (Smoking) which occurs at a higher temperature than aerosolization and can consistently produce a similar level of cannabinoids, is generally the preferred method of delivery for many adolescents [51].

Alternative (non-combusted) methods of aerosolization such as vaporization may be more appealing for some adolescents because of their availability in youth-friendly palatable preparations. The perception of some adolescents is that vaping is more appealing because it is more discreet, healthier, better tasting, less harsh, lower cost, and resulted in better effects [52]. Devices that generate vapor for inhalation of marijuana such as table top and pocket pen devises do so by heating (electronic or otherwise) cannabis products to a vapor that can be inhaled. Even devices such as e-cigarettes that were designed for nicotine can be modified to deliver marijuana products [53]. E-liquids with flavoring can be used to mask the odor of cannabis and make it less detectable [54]. Many of cannabis extracts (oils, vape cartridges, hash) that are vaporized can contain 60% THC, with solid extracts such as wax, budder, shatter, or crumble can exceed 90% [55, 56]. Any of these extracts can be vaporized through an electronic delivery system and e-cigarettes. “Dabbing” which typically involves heating a small amount of extract (dried, concentrated cannabis) either with a tabletop vaporizer (200°C) without combustion (combustion or pyrolysis can destroy a major fraction of THC) by heating a glass rod or nail head with a blowtorch resulting in a vapor to inhale [57]. This can be a complicated method of vaporizing cannabis concentrates that can include a dab rig (modified water pipe for oils and concentrates) a nail attached to the rig to heat the concentrate, a dabber to apply the dab of concentrate to the nail, a dome placed over the nail to contain the vapor, and a blow torch to heat the nail [36]. But dabbing can be simplified with the use of a modified vape pen also known as dab or wax pen. A “dab” is a colloquial name for butane hash oil (BHO) which is a concentrated THC extract generated using butane as a solvent. The concentrate is then vaporized quickly and the user inhales the vapors and swiftly feels the effects. It’s unclear if this method of “dabbing” is inherently more dangerous than ingesting or inhaling flower cannabis (smoking) because of the more concentrated extract. These concentrated extracts can be 20–25% THC to upwards of 80% THC in comparison to smoking dried marijuana leaves which is likely 10–20%. Individuals may “dab” anywhere from a few times to 25–50 times in a brief period until the desired effect is obtained [58]. Similar to the adverse effects of smoking marijuana, risks include blackouts, tachycardia, paranoia, and hallucinations.

Hash, is the oldest form of cannabis extract, is composed of purified trichomes (the tiny hair-like outgrowths on cannabis leaves/flower that appear like sugar dusting on the plant) [39]. Inhalable or vaporized plant, oil or extract that is aerosolized by an electronic heating device may be able to generate a higher blood concentration of THC and likely a corresponding subjective effect although vaping devices can vary in their efficiency in delivering the product. It is important to note that the “strength” of a cannabis product often has few, if any, visual cues so the self-made THC/cannabis products obtained on the streets will likely have variable cannabinoid composition [59].

The pharmacokinetics of smoked and vaporized cannabis/THC produce peak blood concentrations within 3–10 minutes after onset of inhaling with THC being detectable in plasma within seconds after the first puff [35]. Both vaporized and smoked THC produce rapid peak blood concentrations in 30–90 minutes that return to baseline within 2–4 hours [39]. The pharmacodynamic onset of inhaled THC is dose related and the self-reported experiences of intoxication match, to some extent, the onset of peak blood concentration. However, because its high lipophilicity, THC is rapidly redistributed to the tissues, including the brain where it produces its neurocognitive effects. The high lipophilicity of THC also contributes to prolong detection in urine for chronic, everyday users. In certain situations, it may be imperative to obtain blood levels of THC as well as to obtain confirmation for detection of marijuana. It’s important to know that false positive urine screens for THC are possible and include: medications such as Naproxen, Ibuprofen, Promethazine, Riboflavin, Pantoprazole and Ketoprofen; and some baby shampoos and soaps [20].

4.1 Passive inhalation of cannabis smoke

There is evidence that passive inhalation by an infant can indeed result in toxicity as shown in a 13-month-old who appeared altered and ill [60]. The infant was sleeping in the parent’s room where 20 cannabis smokers were engaged in a party for many hours. The infant was subsequently discharged from the hospital and showed marked improvement after 48 hours with just supportive care. Compared to adults, infants have increased minute ventilation relative to their size, which can result in increased absorption. This likely was an enclosed area with poor ventilation and if blood levels and a urine tox screen had been performed on the infant, a THC level and a positive urine screen would have been found. The exposure of the infant to second-hand cannabis smoke is consistent with a systematic review involving passive exposure to second-hand smoke involving adults [61]. In this “meta-analysis”, adults passively exposed to increasing amounts of THC from smoked cannabis, will in kind, also report stronger drug effects and higher levels of THC and metabolites can be found in their urine.

5. Cannabis ingestion

Ingestion of “edibles” are food items made with marijuana or oils infused with THC and come in a variety of forms such as baked goods (brownies, muffins and cookies); candies including gummies, caramels, hard candies, and chocolates; lozenges; or infused beverages [62]. Edibles are becoming more popular because the products are more discreet and convenient, produce no smoke or smell, it eliminates the respiratory risk of inhalation (bronchial irritants and carcinogens), generates no secondhand smoke concerns, and it produces a more prolonged and intense psychoactive effect [47]. Many adolescents are less likely to use edibles because they report more negative effects from edibles [51]. Regardless, data appears to indicate that approximately two thirds of adolescents who use cannabis (smoking) also have used edibles [52]. In addition, edibles pose a more unique problem, especially to the unsuspecting or naive, because there are no other foods, appetizing forms or palatable products in which a drug is purposely infused into it generating the final product. Contributing to the possibility of toxicity is the delayed effects when cannabis products are ingested compared to inhalation. Other concerns include accidental ingestions (especially children), and dose titration as edibles can vary in THC within and across products making it difficult among users to estimate the THC concentration that may lead to overconsumption.

The pharmacokinetics of edible cannabis differ from the profile of inhaled cannabis resulting in peak psychoactive effects being delayed hours after ingestion. As noted above, the effects of inhaled cannabis can be felt within 10 minutes, peak blood concentrations within an hour and complete clearance from the blood within 4 hours. Since adolescents or any adult can feel the effects (pharmacodynamics) of inhaled cannabis within minutes, significant toxicity can occur from consuming edibles if the user expects the same time line. When taken orally, THC (Delta-9 THC) undergoes “first pass effect” as the digestive system absorbs and further bio transforms (metabolize) the drug in the liver and in the process, decreases the availability of the active drug (THC) and generates another active equipotent metabolite (11-OH-THC) as well as the inactive carboxylic acid (THC-COOH) [35]. The hydroxylation of THC by the liver cytochrome P450 system to form 11-OH-THC is a potent psychoactive metabolite that readily crosses the blood brain barrier [63], and may be responsible for the stronger and longer lasting drug effects of edibles in comparison to comparable doses of smoked cannabis [64, 65].

The bioavailability of THC when ingested is 10–20% as much of the cannabinoids contained in cannabis are degraded [20]. The process of absorption, metabolism, and re-distribution generates variable time delay in the onset of effects which may result in the adolescent consuming more than initially intended. Although edibles can produce the same dose-related increments in peak THC blood concentrations and subjective high as inhalation, oral THC may take at least 30 minutes to reach significant blood levels with a peak at 3 hours and clearance from the blood at 12 or more hours [35, 39]. Consequently, oral consumers of edibles generally report longer lasting effects of the cannabis than inhalation as well as more intense and unpleasant side effects which can result in significant toxicity [62, 66, 67].

5.1 Cannabis toxicity from ingestion

Cannabis toxicity from edibles probably results in the majority of visits to the health care system simply because it encompasses all age groups, both young and old. The very young, because toddlers are human vacuum cleaners destined to clean up after adults who left their gummy bears within reach, an unsmoked joint or THC resin on the coffee table or half-eaten cannabis cookie on the floor. If 10 to 30 mg of oral THC is the recommended dose for intoxication in an adolescent/young adult, then a cookie containing approximately 100 mgs of THC that a toddler eats could die from respiratory failure [68]. The adolescent or adult comes to the emergency department because of failure to appreciate the differing THC pharmacokinetic profiles of ingestion vs. inhalation and the user consumed the entire edible cookie after not experiencing the initial effects from ¼ of the intended dose of cookie he was to consume but did not because of delayed effects. Now the anxious adolescent who consumed the entire edible cookie is delirious or severely impaired and is experiencing an unexpected adverse effect in need of at least supportive medical care.

The majority of patients seen for cannabis ingestion will not require any treatment [42, 68, 69]. However, compared to toxicity from inhalation (cannabis), cannabis ingestion will be the mode of exposure that most likely will cause concerning signs and symptoms. Adolescents as well as adults were more likely to intentionally ingest edibles due to overconsumption and poor understanding of the delayed effects and experience tachycardia and CNS excitation that ranged from anxiety, paranoia and panic attacks to altered mental status, psychosis, and seizures with benzodiazepines being the most commonly used medication during care [67, 69]. Treatment for cannabis psychosis in the acute stage including agitation, auditory and visual hallucinations included intramuscular antipsychotics (haloperidol and droperidol), oral risperidone and olanzapine, seclusion as well as benzodiazepines [70]. Most of the other minor interventions will be for nausea and vomiting, fluid hydration and supplemental oxygen. There is no antidote for cannabis toxicity and no way to alter or hasten its metabolism, nor to increase its rate of excretion. The majority of these patients were discharged home from the emergency department with some (<10%) needing hospitalization. Clinical findings in older children and adolescents may include psychosis, ataxia, tremors, nystagmus, mood and attention alterations, excessive motor activity and muscle relaxation [43]. Children (<12 years) were more likely to unintentionally ingest edibles at home and experience CNS sedation with a higher risk of ICU admission and an occasional intubation for CNS depression [42, 69]. For children under the age of 6 years, the most common clinical effects from ingestion included, drowsiness or lethargy, ataxia, agitation or irritability and confusion. The less common but serious effects included respiratory depression, coma and seizure [71]. It is important to realize that cannabis intoxication may be life threatening, especially in the very young [72, 73].

Cannabis intoxication in children should be suspected in an afebrile child, previously known to be healthy, with a clinical presentation that includes drowsiness, lethargy, or coma with no focal neurological findings [72]. Most of the other minor interventions will be for nausea and vomiting, fluid hydration and supplemental oxygen. Although edibles being the most commonly ingested substance, other ingested substances included botanical, concentrates and resins.

There are several studies now that are associating the high percentage of THC with a considerable increase in acute toxicity, especially with an increased risk of psychosis [32, 74, 75].

6. Cannabis during pregnancy and breastfeeding

Cannabis-derived drugs (marijuana) are the most widely used illicit drug in pregnancy and is frequently used to minimize the symptoms of morning sickness [76]. Although marijuana is not listed as a known teratogen, it’s conceivable that THC, acting through the eCB system could result in perturbations of the developing fetus that could adversely affect neurodevelopment. Cannabis exposure during pregnancy does not cause congenital defects such as mental retardation and developmental disabilities as with fetal alcohol syndrome [77]. Very early in the peri-conception period there is some evidence that in utero cannabis exposure may increase the risk of anencephaly [78], although evidence on possible adverse impacts on fetal development and neonatal outcomes is inconsistent. However, there are studies that implicate cannabis in causing neurological impairment, hyperactivity, poor cognitive function, and changes in dopaminergic receptors in children when exposed in utero [79].

Marijuana constituents do pass freely across the placenta and has been shown to concentrate in breastmilk at levels 8 times of that of plasma THC [80]. Endocannabinoids (AEA and 2-AG) are also found in breast milk [81]. While there is clear data showing cannabinoids are expressed in breast milk, there is no concrete evidence that infants exposed to such breast milk have any potential health effects [82]. Although the pharmacokinetics are known regarding the metabolism and plasma concentration after inhalation, intravenous and oral cannabis administration, less is known about the distribution of cannabinoids in breast milk. There is also a tendency for breast feeding moms to increase their cannabis use during the postpartum period and this increase translates to enhanced levels of THC in breast milk [83]. Because there is so little information on cannabis use during pregnancy and postpartum use while breast feeding, the clinician may want to consider harm reduction approach to reduce cannabis use during pregnancy and postpartum [18]. The perception during pregnancy and with postpartum mothers using cannabis that little harm is to come from cannabis use is simply not known and further research is urgently needed. Lower birthweight of the newborn is associated with smoking marijuana during pregnancy, as is smoking cigarettes [84]. Whether or not the oxidative stress caused by smoke is a mechanism of low birth weight or if it is a direct effect of cigarette or marijuana is not known [85].

7. Synthetic cannabinoids and their related toxicities

Synthetic cannabinoids (SCs) are chemically engineered agonists to the CB1 receptor in the endocannabinoid system and are biochemically similar to THC in its post receptor activity but may be chemically/structurally quite different to the THC molecule making it undetectable in urine drug screens. It emerged in the 1970s when researchers were hopeful in developing new treatments for cancer and were synthesized in academic centers and pharmaceutical industries [4]. It wasn’t until 2008 however that investigators first detected the synthetic cannabinoid (JWH-018) in a herbal product that was related to a forensic investigation [5]. Since then, and actually greatly underappreciated before that, SCs have mushroomed in their prevalence and are now readily available on the streets for abuse purposes. SCs are commonly known as synthetic marijuana or synthetic cannabinoid receptor agonists and are sold in brightly colored foil packages and contain finely cut plant material that has been adulterated or ‘sprayed” or soaked with SCs. As such, these SCs are not regulated, there are no “good laboratory practice” associated with the production of SCs by clandestine laboratories, and are classified as Schedule I in the United States based on their chemical structures by the USDEA. The dried plant material used for smoking has no inherent psychotropic effects and are solely a vehicle for delivering the synthetic cannabinoid effect. Initially it was the illegality of marijuana that likely motivated the production of SCs by drug distributers and entrepreneurs to produce compounds that could be marketed to users of marijuana or prospective new users to provide a “legal” alternative to marijuana but still with the desired effects including mood elevation, relaxation, euphoria, or creative thinking [86]. It remains to be seen what impact legalization of marijuana may have in the future regarding the continued use of SCs as the toxicities associated with SCs use by younger audiences are greatly underappreciated.

There are likely over 500 SCs that have been introduced into the recreational markets and they are among the most abused psychoactive substances in Europe and United States [79]. The prevalence of synthetic cannabinoid agonists use by adolescents is reported to be less than 2% in 2021, down from 3 to 10% the year before [37]. Most SCs are very potent and are high-efficiency/full agonists of the CB1 receptors unlike THC, which is considered a partial agonist at the CB1 receptor [3]. However, it is important to realize that the similarities in effects between marijuana and SCs are assumed based only on their receptor binding to CB1 and CB2 as no comparison dosing studies have ever been done. Consequently, the toxicities of SCs are likely underappreciated especially when the adverse effects of marijuana are considered low risk beyond the intoxication effects of low potency cannabis [87]. One author estimates that the risk of an emergency room visit is approximately 30-fold higher with SCs than with cannabis [88]. There is evidence that being a partial or a full agonist of the CB1 receptor along with their binding affinities may correlate with the level of exaggerated psychoactivity [89]. Both SCs and THC activate CB1 receptors which trigger the psychotomimetic effects. Speculation is that the adverse effects and unpredictability of SCs stem from the greater affinity for and increased efficacy at the CB1 receptors, compared to THC, but the relationship is complex [44]. Indeed, the full agonist activity and higher potency of the SCs at the SC1 and SC2 receptors may account in part, for their greater toxicities [90] as it has been estimated that SCs may be 5–80 times more potent at the CB1 receptor than natural cannabis [91]. Besides difference in receptor affinities and whether it is a full or partial agonist at the CB1 receptor, there are likely other differences that may assist in explaining greater toxicity with SCs. First, a remarkable difference in metabolism is that THC has only one active metabolite (11-OH-THC) while SCs can have many metabolites that retain binding affinity and activity at the CB1 receptor [92]. Most of the phytocannabinoids such as THC or cannabinol are metabolized through the liver P450s (CYP2C9, CYP2C19, and CYP3A4) while metabolism of SCs is likely through several metabolic pathways including P450s that may generate metabolites that are injurious to tissues. Although both cannabis and SCs go through the cytochrome P450 system that mediate the phase I reaction, much of the similarities in phase II reaction likely end there as most of cannabis undergoes glucuronidation while SCs undergo multiple processes in both phase I and phase II. However, much of the metabolism of SCs have limited data available. Second, when cannabis is smoked or ingested, all of the additional cannabinoids along with various terpenoids are also inhaled which may provide some complementary or synergistic activity, so called entourage effects [33]. As an example, with increasing potency of cannabis there has been a decrease in CBD levels (increasing THC/CBD ratio) which has been implicated in potentially causing health complications, perhaps because of lessoning of the “entourage effects”. In abusing SCs, there are no other cannabinoids or terpenoids ingested (but many other chemicals certainly could be ingested with SCs) that could “off set”, blunt, modify the activity at the CB1 receptor or provide some neuroprotective effect or some other non-receptor effect, thereby altering the pharmacodynamic full effects of the SCs.

To be clear, SCs are inherently more dangerous, the production of SCs in clandestine labs do not honor the Good Manufacturing Practice regulations so user beware, and the toxicity of SCs can lead to multiple end organ adverse events, including CNS, which can be classified as either physical or psychological effects. Because there are new SCs flooding the markets to avoid the legal system, the likely presence of multiple SCs being ingested at once is likely. No controlled dosing studies have ever been done in humans with SCs, consequently, the pharmacokinetics and pharmacodynamics of SCs are difficult to report with any assurance. Clinicians should suspect the possibility of SCs in an adolescent or young adult who arrives for evaluation with adverse effects similar to cannabis with a neg urine drug screen, including THC. The clinical effects can be highly variable and this diversity of findings may be attributed to the continued variability in composition and concentration of chemicals within SCs [93]. These findings include cardiovascular events, kidney injuries, gastrointestinal problems, neurological events, pulmonary effects, ocular, or psychiatric conditions [3, 86, 94, 95, 96, 97, 98, 99]. At present, the unpredictable effects of SCs and the lack of a clear toxidrome to distinguish SCs from other drugs of abuse makes the differential broad and requires the clinician to first eliminate diverse conditions before settling on the possibility of SCs. In addition, it is also unclear whether the below toxicities are due to the SCs parent molecule, metabolites, or contaminants. See Table 1 for summary of toxicities: synthetic cannabinoids vs. botanical marijuana (Modified from Ford BM, et al) [98].

	Human cannabinoid toxicities
	Synthetic cannabinoids	Botanical marijuana
Cardiovascular
Tachycardia	frequent	uncommon
Arrythmias	possible	rare
Hypertension	possible	rare
Chest pain	possible	rare
Myocardial Infarction/Toxicity	possible	uncommon
Renal
Acute Kidney Injuries	possible	rare
Gastrointestinal
Nausea	frequent	rare
Vomiting (hyperemesis)	frequent	rare
Neurological
Euphoria	frequent	frequent
Appetite Stimulation	frequent	frequent
Nystagmus	possible	possible
Slurred Speech	possible	possible
Lethargy/Ataxia	possible	possible
Confusion	frequent	rare
Seizures	possible	rare
Cerebral Ischemia	possible	rare
Panic Attacks	frequent	rare
Memory Issues	uncommon	frequent
Pulmonary
Acute Resp Distress Syn	possible	rare
Respiratory Depression	possible	possible
Ocular
Conjunctival hyperemia	common	frequent
Psychiatric
Hallucinations (vis/aud)	frequent	rare
Delusions	frequent	rare
Excited Delirium	frequent	rare
Psychosis	possible	uncommon
Agitation	frequent	rare
Anxiety	frequent	rare

Table 1.

Human cannabinoid toxicities: Comparison of synthetic cannabinoid toxicities with botanical marijuana by systems.

7.1 Cardiovascular

Tachycardia and hypertension are the most common clinical effects reported. Associated with tachycardia, there can also be cardiac arrythmias, strokes, chest pain, and myocardial infarctions have also been reported even in adolescents and young adults with no previous cardiac issues. Both bradycardia and hypotension are possible. Other than tachycardia, in comparison to toxicity from marijuana, the other associated cardiovascular toxicities from SCs are not generally reported with marijuana. However, myocardial infarctions have been reported in marijuana smokers and appears to be especially noted during the first hour of exposure.

7.2 Kidney injuries

In the settings of acute toxicity from SCs, there have been numerous reports of acute kidney injuries including elevated serum creatinine, proteinuria, hematuria, acute tubular injury and acute tubular nephritis, hypokalemia, and rhabdomyolysis. Other metabolic disturbances have also been noted in SCs including metabolic/respiratory acidosis and alkalosis. Similar to the cardiovascular toxicities, no renal toxic effects have generally been reported from marijuana.

7.3 Gastrointestinal

Nausea and vomiting are frequently reported with toxicity from SCs and has occurred with cannabis although not as frequently. In fact, it remains unclear why cannabis may suppress emesis in some people and appears to induce it in others. There is a phenomenon of cannabinoid hyperemesis syndrome (CHS) or cyclic vomiting syndrome (CVS), that appears mostly with inhalation of cannabis/SCs but has been observed most frequently with SCs. This is the result of chronic abuse and symptomatic relief can be obtained with hot showers. The most effective means to end CVS is through complete cessation of cannabis use which may take 2 weeks of abstinence. Patients being evaluated for this should be monitored for dehydration and kidney issues as well as Mallory-Weiss tears. Intravenous Haloperidol or Droperidol or application of capsaicin cream to the abdomen appear to be the most effective drugs to control nausea as conventional antiemetics do not appear to offer much relief [100]. Abdominal pain, diarrhea, xerostomia have been reported and resolve. Mouth issues including periodontal bone disease with gingival enlargement have also been seen in chronic use in both CBs and cannabis [101]. Hepatotoxicity has been noted with the use of some SCs [102]. Few GI issues have been reported with cannabis other than related to emesis.

7.4 Neurological

There are a multitude of neurological clinical effects that are possible with toxicity from SCs. Some of the neurological toxicity findings are found in both acute effects of cannabis and SCs and these include, euphoria, appetite stimulation, slurred speech, ataxia/lethargy, and nystagmus. Acute toxicity from SCs is more likely to exhibit the following neurological findings in comparison to cannabis: confusion, anxiety, panic attacks, agitation, irritability, and seizures. Very recently, there was a publication citing evidence that cannabis may have proconvulsant effects [103]. In addition, the following have been reported in acute toxicity from SCs including self-mutilation, catatonia or psychomotor retardation, and memory disturbances. It should be noted that memory disturbances are commonly observed in cannabis abuse.

7.5 Pulmonary

Severe respiratory depression or tachypnea has been observed, along with pneumothorax and acute respiratory distress syndrome can occur with SCs use. In 2019, there was an outbreak of product use-associated lung injury (so called e-cigarette, or vaping, product use associated lung injury, EVALI) [54]. It was not found to be from any particular cannabis or cannabis extact or SCs, but rather from Vitamin E acetate, a diluent and thickening agent in cannabis-based products. Severe respiratory depression can certainly occur with cannabis ingestion as noted above, especially in toddlers and children. Pneumothorax can also occur from both cannabis and SCs use and may be more of a function in maximizing pulmonary absorption by taking very deep and prolonged breaths. Someone with panic attacks or anxiety may be overlooked when an astute clinician or a chest xray may reveal a reason for their anxiety or panic attack and that is a pneumothorax.

7.6 Ocular

Conjunctival hyperemia and mydriasis have been noted in both toxicity from SCs and cannabis.

7.7 Psychiatric

Hallucinations (visual and auditory), anxiety, delusions, excited delirium, and psychosis in susceptible individuals have been noted to be more common in SCs users than in cannabis users regarding acute effects. Psychosis is a condition in which the individual is not able to think clearly, unable to distinguish between reality and false beliefs or delusions. Similar to psychosis with high potency THC, there may be a dose effect that exists for SCs although research is lacking for SCs and absolute confirmation linking cause and effect regarding THC and psychosis is lacking.

As noted above under “neurological”, more individuals with toxicity from SCs were found to have confusion, anxiety, agitation, irritability, and panic attacks compared to cannabis users [104]. Suicidal thoughts and attempts have also been noted in toxicity from SCs. In some, the overall effects of SCs can resemble those of cannabis, but those presenting to the hospital are doing so because of behavioral abnormalities (agitation, psychosis or severe anxiety) or because of acute illnesses such as those listed above involving other end organs. Psychosis or psychosis-like conditions appear relatively frequently with the use of SCs and may be a direct or indirect effect (parent SCs or metabolites) of their high potency or perhaps due to the absence of CBD, the so-called entourage effect with marijuana. There is now evidence that SCs exposure in adolescents is associated with higher odds of neuropsychiatric morbidity than cannabis exposure [105].

7.8 Clinical treatment

Clinical management frequently involves supportive care, intravenous fluids, electrolyte replenishment, benzodiazepines for seizures, neuroleptics (Haldol or Droperidol) for psychotic symptoms, or agitation not responsive to benzodiazepines. Many patients may need to be admitted if unstable, or if acute agitation/psychosis is not clearing. In most patients, the effects noted above are not life threatening and generally cease in around 8 hours after consumption [106]. It should also be noted that unlike cannabis, SCs are not detected by common urine drug screens.

8. Conclusion

Cannabis use is long standing and is not going away. There are currently two major driving forces that may dictate the health of a subset of our adolescence if allowed. First, are the socioeconomic and legislative changes that are generating cheaper and legally available cannabis products, perhaps under the guise of a falsely reassuring perception in lack of harm. The second driving force that is also concerning is higher potency cannabinoids, whether they be botanically derived or synthetic in derivation, that acutely cause toxicity in the CNS and other end organs where cannabinoid receptors are abundantly expressed and has been discussed in this review with management recommendations. With continued use, cannabinoid agonists may be linked to poor social and behavioral outcomes later in life as well as neurocognitive deficits yet to be determined. The research is lacking, urgently needed, and findings likely subtle and difficult to quantify. The nature of adolescence and young adulthood is experimentation and risk taking but the involvement of the eCB system may now be unlocked during critical periods of neurodevelopment. Exogenous cannabinoid agonists may lead to exaggerated psychoactive effects that could result in the formation of permanent and irreversible neural networks posing issues later in life. Future vulnerabilities may include cannabis use disorder and withdrawal issues in the short term and psychosis, schizophrenia, and addiction in the long term.

Acknowledgments

Much appreciation to Renee Lamoureux and the librarian staff at Essentiahealth, St. Mary’s Hospital, Duluth, Minnesota, USA for their tremendous assistance in completing this manuscript.