Cannabinoid Poisoning

 The most potent cannabinoid, THC, was isolated in the 1960s. Nearly 3 decades later, in the early 1990s, the specific cannabinoid receptors were discovered, CB1 (or Cnr1) and CB2 (or Cnr2).

The CB1 receptors are predominantly located in the brain, with a wide distribution. The highest densities are found in the frontal cerebral cortex (higher functioning), hippocampus (memory, cognition), basal ganglion and cerebellum (movement), and striatum (brain reward). Other brain regions in which the CB1 receptors are found include areas responsible for anxiety, pain, sensory perception, motor coordination, and endocrine function. This distribution is consistent with the clinical effects elicited by cannabinoids.

The CB2 receptor, on the other hand, is located peripherally. Specifically, it is involved in the immune system (splenic macrophages, T and B lymphocytes), peripheral nerves, and the vas deferens.

Both the CB1 and CB2 receptors inhibit adenylate cyclase and stimulate potassium channels. As a result, the CB1 receptors inhibit the release of several neurotransmitters, including acetylcholine, glutamate, norepinephrine, dopamine, serotonin, and gamma–aminobutyric acid (GABA). CB2 receptor signaling is involved in immune and inflammatory reactions.

Potency

In recent decades, the average THC potency of cannabis has increased due to more sophisticated plant breeding and cultivation. ^[3] In the 1970s, the average marijuana cigarette contained approximately 10 mg of THC. Currently, a comparable cigarette contains 60-150 mg. Because the effects of THC are dose dependent, modern cannabis users may experience greater morbidity than their predecessors.

Cannabis is available in several forms. Marijuana is a combination of the cannabis flowering tops and leaves. The THC content is 0.5-5%. Two preparations are possible:

• Bhang – Dried leaves and tops
• Ganja – Leaves and tops with a higher resin content, which results in greater potency

Hashish is dried resin collected from the flowering tops. The THC concentration is 2-20%. Hash oil is a liquid extract; it contains 15% THC.

Sinsemilla is unpollinated flowering tops from the female plant. THC content is as high as 20%. Dutch hemp (Netherweed) has a THC concentration as high as 20%.

Absorption

The route of administration determines the absorption of the cannabis product, as follows:

• Smoking – Onset of action is rapid (within minutes); it results in 10-35% absorption of the available THC; peak plasma concentrations occur within 8 minutes.
• Ingestion – Onset occurs within 1-3 hours (unpredictable); 5-20% is absorbed, due to stomach acid content and metabolism; peak plasma levels occur 2-6 hours after ingestion.

Behavioral effects

THC most commonly produces euphoria, or a "high," including feelings of intoxication and detachment, relaxation, altered perception of time and distance, intensified sensory experiences, laughter, talkativeness, decreased anxiety, decreased alertness, and depression. These effects depend on the dose, expectations of the user, mode of administration, social environment, and personality.

THC triggers dopaminergic neurons in the ventral tegmental area of the brain, a region known to mediate the reinforcing (rewarding) effects. This dopaminergic drive is thought to underlie the reinforcing and addicting properties of this drug.

Dysphoric reactions to cannabis are not uncommon, especially in naive users. Reactions can include severe anxiety or panic, unpleasant somatic sensations, delirium, mania, or paranoia. Anxiety and/or panic are the most common reactions; they are of sudden onset during or shortly after smoking, or they can appear more gradually 1-2 hours after an oral dose. These effects often occur in those who unwittingly consume marijuana (eg. those ingesting baked goods that they did not know contained marijuana). Cannabidiol may mitigate the adverse psychiatric effects of THC. These anxiety/panic reactions usually resolve without intervention.

Although flashbacks, in which the original drug experience (usually dysphoria) is relived weeks or months after use., have been reported, they are uncommon. 

Mental effects

Short-term memory is impaired even after small doses in both naive and experienced users. The deficits appear to be in acquisition of memory, which may result from an attentional deficit, combined with the inability to filter out irrelevant information and the intrusion of extraneous thoughts.

Chronic use can be associated with subtle impairment in cognitive function, which is dependent on dose and duration of use. At present, most of the available data indicate that these cognitive deficits are reversible after more than a week of abstinence.

Immune system effects

Based on extrapolation from in vitro data, cannabis use may impair the immune system's ability to fight off microbial and viral infection. In a dose-dependent fashion, lung macrophage functions, including phagocytosis, migration, and cytokine production, appear to be compromised by cannabis use in vitro. Although cannabinoid receptors are found on human T and B lymphocytes, to date, no conclusive effects have been found on the use of cannabis and the clinical effects related to the presence of these receptors.

Cardiovascular effects

These include the following:

• Naive users may experience a sudden 20-100% rise in heart rate, lasting up to 2-3 hours
• Peripheral vasodilatation causes postural hypotension, which may lead to dizziness or syncope
• Cardiac output increases by as much as 30%, and cardiac oxygen demand is also increased; tolerance to these effects can develop within a few days of use
• Naive users can experience angina; in addition, users with preexisting coronary artery disease or cerebrovascular disease may experience myocardial infarctions, congestive heart failure, and strokes

Respiratory effects

Transient bronchodilatation may occur after an acute exposure. With chronic heavy smoking, users experience increased cough, sputum production, and wheezing. These complaints are augmented by concurrent tobacco use. One study cites that the rate of decline of respiratory function in an 8-year period was greater among marijuana smokers than among tobacco smokers.

Aside from nicotine, marijuana cigarettes contain some of the same components as tobacco smoke, including bronchial irritants, tumor initiators (mutagens), and tumor promoters. The amount of tar in a marijuana cigarette is 3 times the amount in a tobacco cigarette when smoked, with one-third greater deposition in the respiratory tract.

Chronic cannabis use is associated with bronchitis, squamous metaplasia of the tracheobronchial epithelium, and emphysema. These problems have been reported more frequently in cannabis-only users than in tobacco-only users.

Several case reports strongly suggest a link between cannabis smoking and cancer of the aerodigestive system, including the oropharynx and tongue, nasal and sinus epithelium, and larynx.

Most illegally obtained marijuana is contaminated with Aspergillus species, which can cause invasive pulmonary aspergillosis in immunocompromised users.

Reproductive effects

These include the following:

• High-dose THC in animals causes a reversible drop in testosterone levels, decreased sperm production, and compromised sperm motility and viability.

• THC alters the normal ovulatory cycle by decreasing follicle stimulating hormone, luteinizing hormone, and prolactin and impairing sex hormone secretion. ^[4]

• THC crosses the placenta and accumulates in breast milk.

• THC impairs placental development and homeostasis, fetal nourishment and gas exchange. For this reason, it is implicated in low birth weight, growth restriction, pre-eclampsia, spontaneous miscarriage, and stillbirth. Human studies show mixed results, largely from limitations of self-reporting and testing marijuana use. ^{[4, 5]}

• A growing body of evidence suggests permanent, though subtle, effects on memory, informational processing, and executive functions in the offspring of women who use cannabis during pregnancy.

• Children younger than 1 week of age born to mothers who used cannabis during pregnancy had increased incidence of tremors and staring. Children of chronic users (>5 joints per wk) were found to have lower verbal and memory scores at age 2 years.

• Three studies have demonstrated a possible increased risk of nonlymphoblastic leukemia, rhabdomyosarcoma, and astrocytoma in children whose mothers reported using cannabis during their pregnancies.

Psychosis association

Large doses of THC may produce confusion, amnesia, delusions, hallucinations, anxiety, and agitation. Most episodes remit rapidly.

A clear relationship exists between long-term cannabis use and mental health problems, however, it is unclear whether the relationship is causative.  ^[6]  Substance-abusing adolescents commonly suffer one or more comorbid health or behavioral problems. Several studies have demonstrated marijuana abuse to coexist with attention deficit hyperactivity disorder, other learning disabilities, depression, and anxiety. Cohort and well-designed cross-sectional studies suggest a modest association between early, regular, or heavy cannabis use and depression. ^[7]

An association exists between cannabis use and schizophrenia. A prospective study of 50,000 Swedish conscripts found a dose-response relationship between the frequency of cannabis use by age 18 and the risk of a diagnosis of schizophrenia over the subsequent 15 years. ^[8] Five prospective studies with well-defined samples looked at cannabis use and psychosis and concluded an overall 2-fold increase in the relative risk for developing schizophrenia. Yet, cannabis use appears to be neither necessary nor sufficient to cause schizophrenia. Among people who already have schizophrenia, cannabis use is predicted to worsen psychotic symptoms. Strains of cannabis that are high in CBD may be less likely to trigger psychotic symptoms. 

Metabolism and elimination

THC is metabolized via the hepatic cytochrome P₄₅₀ (CYP) system. THC is metabolized into an active compound, 11-hydroxy-THC (11-OH-THC), which is further metabolized into inactive forms.

The elimination half-life of THC can range from 2-57 hours following intravenous use and inhalation. The half-life of 11-OH-THC, the active metabolite of THC, is 12-36 hours. Intravenous use or inhalation results in 15% excretion in the urine and 25-35% in the feces. Within 5 days, nearly 90% of THC is eliminated from the body.

The duration of acute clinical effects is mediated by drug redistribution into body fat stores rather than metabolism or elimination. 

Tolerance

Repeated use over days to weeks induces considerable tolerance to the behavioral and psychological effects of cannabis. Several studies have noted partial tolerance to its effect on mood, memory, motor coordination, sleep, brain wave activity, blood pressure, temperature, and nausea. The rate of tolerance depends on the dose and frequency of administration. The casual cannabis user experiences more impairment in cognitive and psychomotor function to a particular acute dose than heavier, chronic users. The desired recreational high from cannabis also diminishes with use, prompting many users to escalate the dose.

Pharmacologically, chronic use results in the downregulation of the CB1 receptor in several regions of the rat brain. No correlations have been made in human physiology.

Toxicity

Acute cannabis toxicity results in the following:

• Difficulty with coordination
• Decreased muscle strength
• Decreased hand steadiness
• Postural hypotension
• Lethargy
• Decreased concentration
• Slowed reaction time
• Slurred speech
• Conjunctival injection

Although acute toxicity is benign in the average adult, the same cannot always be said for children. In a systematic review of unintentional cannabis ingestion in children under 12 years of age, the most common presenting signs and findings were lethargy, hypotonia, hypoventilation, tachycardia, ataxia, and mydriasis.  Vomiting and seizures have also been reported, as well as paradoxical hyperactivity and irritability. Treatment is largely supportive, including intubation in some instances. Having a clinical suspicion for cannabis toxicity is important as these patients may otherwise undergo lengthy and invasive evaluations for their symptoms. ^[9]  

Unintentional ingestion in children has been on the rise with the increase in availability afforded by state de-criminalization. A majority of these cases are from unintentional ingestion of edibles, many of which have colorful packaging and are made to look like cookies and candies. A retrospective review of 80 children under 6 years old who ingested edible cannabis reported that 1.7 mg/kg or greater correlates with severe and prolonged toxicity. ^[10]

Nationwide, children's exposure to cannabis products rose 148% from 2006 to 2013. In states allowing medical cannabis, that figure increased by 610%

Adverse reactions

Chronic users may experience paranoia, panic disorder, fear, or dysphoria. Transient psychotic episodes may also occur with cannabis use. These psychiatric effects may be less likely to occur with strains that contain higher concentrations of CBD. 

Ventricular tachycardia is also reported in association with use of this drug, but is unclear whether the association is causative. 

Dependence and withdrawal

Nearly 7-10% of regular users become behaviorally and physically dependent on cannabis. Furthermore, early onset of use and daily/weekly use correlates with future dependence. According to the National Institute on Drug Abuse (NIDA), 100,000 people are treated annually for primary (may be self-perceived) marijuana abuse. ^[11]

Animal studies demonstrate withdrawal symptoms with use of CB1 receptor antagonists. However, in humans, the withdrawal syndrome is not well characterized. Classic manifestations—which may develop upon withdrawal after as little as 1 week of daily use—include the following ^[12] :

• Irritability
• Restlessness
• Insomnia
• Anorexia
• Nausea
• Sweating
• Salivation
• Increased body temperature
• Tremors
• Weight loss

Frequency

United States

Marijuana became the major drug of abuse in the 1960s. Its use peaked in the late 1970s. According to the NIDA-funded Monitoring the Future survey, the peak year of use occurred in 1979, with 60.4% of 12th-grade students having used cannabis in their lifetimes, 50.8% in the preceding year, and more than 10.3% on a daily basis. Cannabis use began a continuous decline, with the lowest use occurring in 1992. At that time, 32.6% of 12th-grade students reported ever using cannabis, 21.9% reported use in the preceding year, and 1.9% reported using on a daily basis. The decline in use was attributed to perceived risk and to personal disapproval of drugs.

From 1992-1997, marijuana use increased dramatically and then plateaued in the last 2 years. In 1999, 22% of 8th-grade students and 49.7% of 12th-grade students reported ever using cannabis. Daily use was 1.4% and 6%, respectively. ^[13]

Since the turn of the 21st century, marijuana use by middle and high school students has fluctuated. In 2019, daily use in the younger grades increased significantly. In addition, teens’ perceptions of the risks of marijuana use have steadily declined over the past decade. In 2019, 11.8% of 8th graders reported marijuana use in the past year and 6.6% in the past month. Among 10th& graders, 28.8% had used marijuana in the past year and 18.4% in the past month. Rates of use among 12th graders were highest, with 35.7% having used marijuana during the year prior to the survey and 22.3% in the past month; 6.4% said they used marijuana daily or near-daily. ^[14]

In 2022, an estimated 8.3% of 8th graders, 19.5% of 10th graders, and 30.7% of 12th graders reported using cannabis/hashish in the past 12 months. In addition, the use of vaping devices to consume cannabis products has become common with 20.6% of 12th graders reporting that they vaped marijuana in the past year and 2.1% reporting that they did so daily. ^[15]

In 2022, 3419 single-substance exposures to CBD, 3994 exposures to marijuana dried plant and 10,512 exposures to marijuana edibles were reported to the National Poison Data System of the American Association of Poison Control Centers (AAPCC). About 62% of all cannabinoid exposures were unintentional, and 68% of patients were treated at a healthcare facility. ^[16]

The Drug Abuse Warning Network (DAWN) estimated that in 2011, nearly 456,000 drug-related emergency department (ED) visits in which marijuana use was mentioned in the medical record occurred in the United States; however, mentions of marijuana in medical records do not necessarily indicate that these emergencies were directly related to marijuana intoxication. Marijuana accounted for 146.2 visits per 100,000 population. ^{[14, 17]} DAWN found that cannabis was reported in 11.9% (more than 918,000) of the estimated 7,714,521 drug-related ED visits in the US in 2022. ^[18] The increase in ED visits may be due to an increase in the use of marijuana, an increase in the potency of marijuana (ie, amount of THC it contains), or to some other factors

International

According to the United Nations, an estimated 219 million people used cannabis in 2021, making it the most used drug globally. In comparison, 60 million people used opioids in 2021. ^[19] European monitoring noted in a 2023 report that among 15-24 year olds, use in the past year was 18.2% (8.6 million). Among 15-64 year olds, 1.3% (3.7 million) are daily or almost daily cannabis users. ^[20]

Mortality/Morbidity

In 2014, ingested marijuana was thought to be a chief contributing factor in the death of a 19-year-old man in Colorado. According to the investigation, the marijuana-naïve patient bought a cookie containing 65 mg of THC in 6.5 servings. He reportedly ate one serving and, upon not feeling any effects 30-60 minutes later, ate the remainder of the cookie. Over the next 2.5 hours, the patient became erratic, hostile, and jumped from a 4th floor balcony, later dying from his injuries. At autopsy, only cannabinoids were found in his system. ^[21]

This case report highlights the delay and variability in absorption rates and intoxication with ingesting THC products. Effects take 1-2 hours to peak with ingestion, vs 5-10 minutes with smoking.

Race-, Sex-, and Age-related Demographics

DAWN reported that in the US in 2022, the rate of cannabis-related ED visits was 660 per 100,000 in Blacks, 153 per 100,000 in Whites, and 91 per 100,000 in American Indians or Alaskan Natives. Males accounted for 60.4% of cannabis-related ED visits, and females accounted for 39.4%. The rate of cannabis-related ED visits was significantly higher in individuals age 18 to 25 years (597 per 100,000); however, the percentage of cannabis-related ED visits was highest in patients 26 to 44 years old  (45.5%). ^[18] In Europe, among 15-34 year-olds, an estimated 2.1 million are daily or almost daily cannabis users; approximately 75% are male. ^[20]

Most cannabis users begin use when younger than 20 years of age, with the peak incidence of onset between 16 and 18 years. Most stop using marijuana by their mid to late 20s. Only about 10% become daily users.

THC has a long half-life and widespread neurocognitive effects. However, Hooper et al found that adolescents with cannabis use disorder who were in full remission after successful first treatment (n=33) showed no difference in intellectual, neurocognitive, and academic achievement compared with healthy adolescents (n=43) or controls who had psychiatric disorders without a history of substance use disorder (n=37). These researchers concluded that adolescents with cannabis use disorder may not be vulnerable to THC-related neuropsychological deficits once they achieve remission from all drugs for at least 30 days. ^[22]

Some evidence suggests that heavy marijuana use during adolescence may lead to increased health problems in later adulthood. These may include both physical disorders (eg, respiratory illness) and mental disorders. For example, Meier et al reported that people who started smoking marijuana heavily in their teens and had an ongoing cannabis use disorder lost an average of 8 IQ points between ages 13 and 38, and that those who quit marijuana as adults did not fully recover those losses. ^[23]

On the other hand, the Pittsburgh Youth Study, which  tracked 408 boys  (54% black, 42% white) from adolescence into their mid-30s found no differences in any of the mental or physical health outcomes measured, regardless of the amount or frequency of marijuana used during adolescence. The mental health outcomes included anxiety and mood and psychotic disorders. The physical health outcomes included asthma, allergies, headaches, high blood pressure, limitations in physical activities, physical injuries, and concussions. ^{[24, 25]}

These researchers hypothesized that the overall pattern of use between adolescence and adulthood, which their study focused on, may be a less important than other factors (eg, cumulative tetrahydrocannabinol exposure, age of initiation of use, or use at a particular age) for predicting negative health outcomes. ^{[24, 25]}

Educate all patients with cannabis use or abuse about the adverse effects of this drug. Encouraging cessation is equally important.

An effort should be made to educate patients on the adverse effects of cannabis use, which include the following:

• Impaired attention, memory, and psychomotor performance during intoxication
• Possible subtle changes in attention and memory with chronic use
• Increased risk of motor vehicle collisions if driving while intoxicated
• Chronic bronchitis and histopathologic changes of the nasal cavity or respiratory tract that may be cancerous precursors

For patient education information, see Substance Abuse.