- Author: Linda Russo, MD; Chief Editor: Duane C Caneva, MD, MSc more...
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 can be smoked as a cigarette, known colloquially as a "joint," or in water pipes or “bongs”. This plant has been used for several thousands of years both recreationally and medicinally. See the image below.
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.
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. Large doses of THC may produce confusion, amnesia, delusions, hallucinations, anxiety, and agitation, but most episodes remit rapidly. Long-term users may experience paranoia, panic disorder, fear, or dysphoria.
The relationship of cannabis to other drugs of abuse is described in two conflicting models. The "gateway" theory of the development of abuse describes the escalation of drug use from adolescence to adulthood. According to this theory, a person will progress from legal drugs, such as alcohol and cigarettes, to illicit drugs, such as marijuana.
In contrast, the common liability to addiction (CLA) model posits that a set of set of factors (which may include psychological characteristics, social environment, and genetic tendencies) is associated with risk for all types of substance use disorders. In this model, which is supported by increasing evidence, a sequence of use can start with any substance, legal or illegal.
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.
In recent decades, the average THC potency of cannabis has increased due to more sophisticated plant breeding and cultivation. 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 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%.
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.
THC 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 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.
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 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.
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
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.
These include the following:
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 by decreasing follicle stimulating hormone, luteinizing hormone, and prolactin and impairing sex hormone secretion. 
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.
Large doses of THC may produce confusion, amnesia, delusions, hallucinations, anxiety, and agitation. Most episodes remit rapidly.
However, a clear relationship exists between long-term cannabis use and mental health problems. 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.
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.
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.
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.
Acute cannabis toxicity results in the following:
Difficulty with coordination
Decreased muscle strength
Decreased hand steadiness
Slowed reaction time
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.[9, 10]
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.
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 :
Increased body temperature
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 leveled off 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.
Since the turn of the 21st century, marijuana use by middle and high school students has fluctuated, but it has held steady in recent years. In 2014, 15.6% of 8th-grade students and 44.4% of 12th-grade students reported ever using cannabis, and daily use was 1.0% and 5.8%, respectively.
The Drug Abuse Warning Network (DAWN) reported 21% increase from 2009 to 2011 in medical emergencies possibly related to marijuana use. 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, 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, 15] 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
The United Nations Office on Drugs and Crime estimates that in 2012, 2.7-4.9% of the world's population aged 15-64 years used cannabis, corresponding to 125 to 227 million people. European monitoring noted in a 2013 report anywhere from 0.8- 40% fo 15-24 years olds having a lifetime use. Prevalence rates were considerably higher than the global average in West and Central Africa, North America, Oceania and, to a lesser extent, Western and Central Europe.
In March of 2014, ingested marijuana was a chief contributing factor in the death of a 19-year-old man in Colorado. According to the investigation, the marijuana-naive 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.
This case report highlights the delay and variability in absorption rates and intoxication with ingesting THC products, taking 1-2 hours to peak vs 5-10 minutes when smoked.
Race-, Sex-, and Age-related Demographics
No differences are reported in patterns of cannabis use according to racial or ethnic background. Little information is available regarding gender differences in cannabis use. Of drug-related emergency department visits in 2011 in which the medical record mentioned marijuana use, about two-thirds of patients were male and 13% were 12-17 years old.
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.
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