Cannabinoid Poisoning

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Cannabinoid Poisoning

Background Cannabis sativa is the hemp plant from which marijuana (leaves, stems, seeds) are derived. The term marijuana became popular in the 1930s; it was originally a slang word for the medicinal part of cannabis smoked by Mexican soldiers. Hemp refers to the roots, stalk, and stems of the plant, which can be used to make rope and twine. The most potent form of this plant's extracts is hash oil, a liquid. The dried resins are referred to as "hashish". The dried flowering tops and leaves are smoked as a cigarette, known as a "joint" or a "reefer". This plant has been used for several thousands of years both recreationally and medicinally. See the image below.

Flowering top of cannabis plant.

Likewise, cannabinoids can be used as biological warfare, as they produce predominately behavioral effects. Although they are not a likely choice in warfare, cannabinoids have many active metabolites that can prolong their effects. More than 400 active compounds have been isolated from the C sativa plant. Sixty active compounds are unique to the plant and are collectively known as cannabinoids. Delta-9-tetrahydrocannanbinol (THC) is the most psychoactive cannabinoid, producing euphoria, relaxation, intensification of ordinary sensory experiences, perceptual alterations, diminished pain, and difficulties with memory and concentration. The "Gateway" theory of the development of abuse describes the escalation of drug use from adolescence to adulthood. According to this theory, one progresses from legal drugs, such as alcohol and cigarettes, to illicit drugs, such as marijuana. A cross-sectional study conducted recently demonstrated that a twin who used cannabis by age 17 was 2-5 times more likely to use other drugs, or develop alcohol dependence than his non-cannabis using twin.

Pathophysiology 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 CR1 receptors inhibit the release of several neurotransmitters, including acetylcholine, glutamate, norepinephrine, dopamine, serotonin, and gamma–aminobutyric acid (GABA). CR2 receptor signaling is involved in immune and inflammatory reactions.

Potency In the last decade, the average THC potency of cannabis has increased due to more sophisticated plant breeding and cultivation.[1] In the 1970s, the average marijuana cigarette contained approximately 10 mg of THC. Today, 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 the following forms: Marijuana is a combination of the C sativa 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. 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. Synthetic forms include the following[2, 3] : Dronabinol (Marinol) – 10% absorption; peak concentration 2-3 hours after ingestion Nabilone (Cesanet) – Up to 90% absorption; peak concentration in 2 hours after ingestion

Behavioral effects THC produces euphoria, or "high," including feelings of intoxication and detachment, relaxation, altered perception of time and distance, intensified sensory experiences, laughter, talkativeness, decreased anxiety,

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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 anxiety/panic reactions usually resolve without intervention. Flashbacks occasionally occur in which the original drug experience (usually dysphoria) is relived weeks or months after use.

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 Cannabis use can 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. This has been demonstrated in limited human in vitro studies. 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 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%. In addition, the 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 sites 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 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 High-dose THC in animals causes a drop in testosterone levels, decreased sperm production, and compromised sperm motility and viability. THC alters the normal ovulatory cycle. Cannabis administration during pregnancy reduces birthweight in animals. However, studies are equivocal in humans. No evidence exists that cannabis increases the risk of birth defects. 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 are rapidly remitting. A clear relationship exists between cannabis use and mental health.[4] Substance-abusing adolescents commonly suffer one or more comorbid health or behavioral problems. Several studies have demonstrated marijuana abuse to coexist with attention deficit Author:hyperactivity Ani Aydin, MD; Chief Editor: Robert G Darling, MD, FACEP and more... disorder, other learning disabilities, depression, anxiety. Cohort and well-designed cross-sectional studies suggest a modest association between early, regular, or heavy cannabis use Updated: Jul 11, and2013 depression. 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. 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.

Cannabinoid Poisoning

Metabolism and elimination http://emedicine.medscape.com/article/833828-overview#showall

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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.

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 CR1 receptor in several regions of the rat brain. No correlations have been made in human physiology.

Toxicity Acute cannabis toxicity results in difficulty with coordination, decreased muscle strength, decreased hand steadiness, postural hypotension, lethargy, decreased concentration, slowed reaction time, slurred speech, and conjunctival injection. Although acute toxicity is benign in the average adult, the same cannot be said for children. A 250-1000 mg ingestion of hashish (up to 20% THC concentration) can result in obtundation within 30 minutes, apnea, bradycardia, cyanosis, or hypotonia in children.[5, 6]

Adverse reactions Chronic users may experience paranoia, panic disorder, fear, or dysphoria. Transient psychotic episodes may also occur with cannabis use. Of great clinical significance, ventricular tachycardia has also been associated with use of this drug.

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.[7] Animal studies demonstrate withdrawal symptoms with use of CB1 receptor antagonists. However, in humans, the withdrawal syndrome is not well characterized. Classically, associated symptoms include irritability, restlessness, insomnia, anorexia, nausea, sweating, salivation, increased body temperature, tremors, and weight loss following as little as 1 week of daily use.

Epidemiology Frequency United States Marijuana became the major drug of abuse in the 1960s. Its use peaked in the late 1970s. According to the NIDAfunded 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 leveled off in the last 2 years. Figures from 1999 reveal that 22% of 8th-grade students and 49.7% of 12th-grade students reported ever using cannabis. Daily use was 1.4% and 6%, respectively.[8] In 1998, the NIDA-sponsored Community Epidemiology Work Group investigated the rates of emergency department mentions of marijuana use in 20 metropolitan areas. Cities with the highest rates included Dallas (63.9%), Boston (44.1%), Denver (40.0%), San Diego (35.1%), and Atlanta (31.1%). The prevalence of marijuana use has increased significantly in the early 2000s. A recent study found a 1.1% risk of marijuana abuse and 0.3% dependence in 40,000 US adults surveyed for one year. In addition, a strong association was noted between marijuana abuse/dependence and Axis I and II disorders. International Prevalence of cannabis use among young people has increased markedly over the last decade in the United Kingdom. Surveys indicate that more than 40% of adolescents aged 15-16 years and 59% of students aged 18 years have experimented at least once with marijuana. In Canada, rates of use are lower, with a national telephone survey revealing that 23% of students reported ever using cannabis. Limited data on cannabis use in Africa, Asia, Central America, and South America, and Middle Eastern countries suggest that these countries have lower rates of lifetime use than most western countries.

Mortality/Morbidity No cases of mortality are reported from cannabis use in adults. One theory is that since cannabinoid receptors are scant in the lower brain stem, where cardiovascular and respiratory functions are controlled, acute cardiorespiratory dysfunction is unlikely.[9]

Race No differences are reported in patterns of cannabis use according to racial or ethnic background.

Sex

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Little information is available regarding gender differences in cannabis use. In a 1995 US study, 6.5% of females and 10.5% of males aged 12 years and older reported marijuana use in the previous year.

Age 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. The Community Epidemiology Work Group, sponsored by NIDA, studied the rates of marijuana use in patients evaluated in emergency departments of 20 metropolitan areas. The highest increase in use was among adolescents aged 12-17 years.

Contributor Information and Disclosures Author Ani Aydin, MD Staff Physician, Department of Emergency Medicine, Bellevue Hospital/New York University Medical Center Ani Aydin, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Emergency Physicians, American Medical Association, Emergency Medicine Residents Association, and Society for Academic Emergency Medicine Disclosure: Nothing to disclose. Coauthor(s) Jessica A Fulton, DO Assistant Professor of Emergency Medicine, Assistant Residency Director, New York University and Bellevue Hospital Center; Medical Director of Chemical Biological Radiological Nuclear Explosives (CBRNE) Academy, Bellevue Hospital Center and New York City Department of Health and Mental Hygiene Jessica A Fulton, DO is a member of the following medical societies: American College of Medical Toxicology Disclosure: Nothing to disclose. Specialty Editor Board Suzanne White, MD Medical Director, Regional Poison Control Center at Children's Hospital, Program Director of Medical Toxicology, Associate Professor, Departments of Emergency Medicine and Pediatrics, Wayne State University School of Medicine Suzanne White, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Clinical Toxicology, American College of Epidemiology, American College of Medical Toxicology, American Medical Association, and Michigan State Medical Society Disclosure: Nothing to disclose. Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Medscape Salary Employment Rick Kulkarni, MD Attending Physician, Department of Emergency Medicine, Cambridge Health Alliance, Division of Emergency Medicine, Harvard Medical School Rick Kulkarni, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine Disclosure: WebMD Salary Employment John D Halamka, MD, MS Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine Disclosure: Nothing to disclose. Chief Editor Robert G Darling, MD, FACEP Adjunct Clinical Assistant Professor of Military and Emergency Medicine, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Associate Director, Center for Disaster and Humanitarian Assistance Medicine Robert G Darling, MD, FACEP is a member of the following medical societies: American College of Emergency Physicians, American Medical Association, American Telemedicine Association, and Association of Military Surgeons of the US Disclosure: Nothing to disclose. Additional Contributors The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors, Gregory R Bell, MD, and Alan H Hall, MD, to the development and writing of this article.

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