What is marijuana?
Marijuana refers to the dried leaves, flowers, stems, and seeds from the Cannabis sativa or Cannabis indicaplant. The plant contains the mind-altering chemical THC and other similar compounds. Extracts can also be made from the cannabis plant (see "Marijuana Extracts").
Marijuana is the most commonly used illicit drug in the United States.1 Its use is widespread among young people. In 2015, more than 11 million young adults ages 18 to 25 used marijuana in the past year.1 According to the Monitoring the Future survey, rates of marijuana use among middle and high school students have dropped or leveled off in the past few years after several years of increase. However, the number of young people who believe regular marijuana use is risky is decreasing.2
Legalization of marijuana for medical use or adult recreational use in a growing number of states may affect these views. Read more about marijuana as medicine in our DrugFacts: Marijuana as Medicine.
Photo by ©Shutterstock/Stephen OrsilloHow do people use marijuana?
People smoke marijuana in hand-rolled cigarettes (joints) or in pipes or water pipes (bongs). They also smoke it in blunts—emptied cigars that have been partly or completely refilled with marijuana. To avoid inhaling smoke, some people are using vaporizers. These devices pull the active ingredients (including THC) from the marijuana and collect their vapor in a storage unit. A person then inhales the vapor, not the smoke. Some vaporizers use a liquid marijuana extract.
People can mix marijuana in food (edibles), such as brownies, cookies, or candy, or brew it as a tea. A newly popular method of use is smoking or eating different forms of THC-rich resins (see "Marijuana Extracts").
Marijuana Extracts
- hash oil or honey oil—a gooey liquid
- wax or budder&mdsh;a soft solid with a texture like lip balm
- shatter—a hard, amber-colored solid
These extracts can deliver extremely large amounts of THC to the body, and their use has sent some people to the emergency room. Another danger is in preparing these extracts, which usually involves butane (lighter fluid). A number of people have caused fires and explosions and have been seriously burned from using butane to make extracts at home.3,4
How does marijuana affect the brain?
Marijuana has both short-and long-term effects on the brain.
Short-Term Effects
When a person smokes marijuana, THC quickly passes from the lungs into the bloodstream. The blood carries the chemical to the brain and other organs throughout the body. The body absorbs THC more slowly when the person eats or drinks it. In that case, they generally feel the effects after 30 minutes to 1 hour.
THC acts on specific brain cell receptors that ordinarily react to natural THC-like chemicals. These natural chemicals play a role in normal brain development and function.
Marijuana overactivates parts of the brain that contain the highest number of these receptors. This causes the "high" that people feel. Other effects include:
- altered senses (for example, seeing brighter colors)
- altered sense of time
- changes in mood
- impaired body movement
- difficulty with thinking and problem-solving
- impaired memory
- hallucinations (when taken in high doses)
- delusions (when taken in high doses)
- psychosis (when taken in high doses)
Long-Term Effects
Marijuana also affects brain development. When people begin using marijuana as teenagers, the drug may impair thinking, memory, and learning functions and affect how the brain builds connections between the areas necessary for these functions. Researchers are still studying how long marijuana's effects last and whether some changes may be permanent.
For example, a study from New Zealand conducted in part by researchers at Duke University showed that people who started smoking marijuana heavily in their teens and had an ongoing marijuana use disorder lost an average of 8 IQ points between ages 13 and 38. The lost mental abilities didn't fully return in those who quit marijuana as adults. Those who started smoking marijuana as adults didn't show notable IQ declines.5
In another recent study on twins, those who used marijuana showed a significant decline in general knowledge and in verbal ability (equivalent to 4 IQ points) between the preteen years and early adulthood, but no predictable difference was found between twins when one used marijuana and the other didn't. This suggests that the IQ decline in marijuana users may be caused by something other than marijuana, such as shared familial factors (e.g., genetics, family environment).6 NIDA’s Adolescent Brain Cognitive Development (ABCD) study, a major longitudinal study, is tracking a large sample of young Americans from late childhood to early adulthood to help clarify how and to what extent marijuana and other substances, alone and in combination, affect adolescent brain development. Read more about the ABCD study on our Longitudinal Study of Adolescent Brain and Cognitive Development (ABCD Study)webpage.
A Rise in Marijuana’s THC Levels
The amount of THC in marijuana has been increasing steadily over the past few decades.7 For a person who's new to marijuana use, this may mean exposure to higher THC levels with a greater chance of a harmful reaction. Higher THC levels may explain the rise in emergency room visits involving marijuana use.
The popularity of edibles also increases the chance of harmful reactions. Edibles take longer to digest and produce a high. Therefore, people may consume more to feel the effects faster, leading to dangerous results.
Higher THC levels may also mean a greater risk for addiction if people are regularly exposing themselves to high doses.
What are the other health effects of marijuana?
Marijuana use may have a wide range of effects, both physical and mental.
Physical Effects
- Breathing problems. Marijuana smoke irritates the lungs, and people who smoke marijuana frequently can have the same breathing problems as those who smoke tobacco. These problems include daily cough and phlegm, more frequent lung illness, and a higher risk of lung infections. Researchers so far haven't found a higher risk for lung cancer in people who smoke marijuana.8
- Increased heart rate. Marijuana raises heart rate for up to 3 hours after smoking. This effect may increase the chance of heart attack. Older people and those with heart problems may be at higher risk.
- Problems with child development during and after pregnancy. One study found that about 20% of pregnant women 24-years-old and younger screened positive for marijuana. However, this study also found that women were about twice as likely to screen positive for marijuana use via a drug test than they state in self-reported measures.9 This suggests that self-reported rates of marijuana use in pregnant females is not an accurate measure of marijuana use and may be underreporting their use. Additionally, in one study of dispensaries, nonmedical personnel at marijuana dispensaries were recommending marijuana to pregnant women for nausea, but medical experts warn against it. This concerns medical experts because marijuana use during pregnancy is linked to lower birth weight10 and increased risk of both brain and behavioral problems in babies. If a pregnant woman uses marijuana, the drug may affect certain developing parts of the fetus's brain. Children exposed to marijuana in the womb have an increased risk of problems with attention,11memory, and problem-solving compared to unexposed children.12 Some research also suggests that moderate amounts of THC are excreted into the breast milk of nursing mothers.13 With regular use, THC can reach amounts in breast milk that could affect the baby's developing brain. More research is needed. Read our Marijuana Research Report for more information about marijuana and pregnancy.
- Intense Nausea and Vomiting. Regular, long-term marijuana use can lead to some people to develop Cannabinoid Hyperemesis Syndrome. This causes users to experience regular cycles of severe nausea, vomiting, and dehydration, sometimes requiring emergency medical attention.14
Mental Effects
Long-term marijuana use has been linked to mental illness in some people, such as:
- temporary hallucinations
- temporary paranoia
- worsening symptoms in patients with schizophrenia—a severe mental disorder with symptoms such as hallucinations, paranoia, and disorganized thinking
Marijuana use has also been linked to other mental health problems, such as depression, anxiety, and suicidal thoughts among teens. However, study findings have been mixed.
Are there effects of inhaling secondhand marijuana smoke?
Failing a Drug Test?
While it's possible to fail a drug test after inhaling secondhand marijuana smoke, it's unlikely. Studies show that very little THC is released in the air when a person exhales. Research findings suggest that, unless people are in an enclosed room, breathing in lots of smoke for hours at close range, they aren't likely to fail a drug test.15,16 Even if some THC was found in the blood, it wouldn't be enough to fail a test.
Getting high from passive exposure?
Similarly, it's unlikely that secondhand marijuana smoke would give nonsmoking people in a confined space a high from passive exposure. Studies have shown that people who don't use marijuana report only mild effects of the drug from a nearby smoker, under extreme conditions (breathing in lots of marijuana smoke for hours in an enclosed room).17
Other Health Effects?
More research is needed to know if secondhand marijuana smoke has similar health risks as secondhand tobacco smoke. A recent study on rats suggests that secondhand marijuana smoke can do as much damage to the heart and blood vessels as secondhand tobacco smoke.20But researchers haven't fully explored the effect of secondhand marijuana smoke on humans. What they do know is that the toxins and tar found in marijuana smoke could affect vulnerable people, such as children or people with asthma.
How Does Marijuana Affect a Person's Life?
Compared to those who don't use marijuana, those who frequently use large amounts report the following:
- lower life satisfaction
- poorer mental health
- poorer physical health
- more relationship problems
People also report less academic and career success. For example, marijuana use is linked to a higher likelihood of dropping out of school.18 It's also linked to more job absences, accidents, and injuries.19
Is marijuana a gateway drug?
Use of alcohol, tobacco, and marijuana are likely to come before use of other drugs.21,22 Animal studies have shown that early exposure to addictive substances, including THC, may change how the brain responds to other drugs. For example, when rodents are repeatedly exposed to THC when they're young, they later show an enhanced response to other addictive substances—such as morphine or nicotine—in the areas of the brain that control reward, and they're more likely to show addiction-like behaviors.23,24
Although these findings support the idea of marijuana as a "gateway drug," the majority of people who use marijuana don't go on to use other "harder" drugs. It's also important to note that other factors besides biological mechanisms, such as a person’s social environment, are also critical in a person’s risk for drug use and addiction. Read more about marijuana as a gateway drug in our Marijuana Research Report.
Can a person overdose on marijuana?
An overdose occurs when a person uses enough of the drug to produce life-threatening symptoms or death. There are no reports of teens or adults dying from marijuana alone. However, some people who use marijuana can feel some very uncomfortable side effects, especially when using marijuana products with high THC levels. People have reported symptoms such as anxiety and paranoia, and in rare cases, an extreme psychotic reaction (which can include delusions and hallucinations) that can lead them to seek treatment in an emergency room.
While a psychotic reaction can occur following any method of use, emergency room responders have seen an increasing number of cases involving marijuana edibles. Some people (especially preteens and teens) who know very little about edibles don't realize that it takes longer for the body to feel marijuana’s effects when eaten rather than smoked. So they consume more of the edible, trying to get high faster or thinking they haven't taken enough. In addition, some babies and toddlers have been seriously ill after ingesting marijuana or marijuana edibles left around the house.
Is marijuana addictive?
Marijuana use can lead to the development of a substance use disorder, a medical illness in which the person is unable to stop using even though it's causing health and social problems in their life. Severe substance use disorders are also known as addiction. Research suggests that between 9 and 30 percent of those who use marijuana may develop some degree of marijuana use disorder.25 People who begin using marijuana before age 18 are four to seven times more likely than adults to develop a marijuana use disorder.26
Many people who use marijuana long term and are trying to quit report mild withdrawal symptoms that make quitting difficult. These include:
- grouchiness
- sleeplessness
- decreased appetite
- anxiety
- cravings
What treatments are available for marijuana use disorder?
No medications are currently available to treat marijuana use disorder, but behavioral support has been shown to be effective. Examples include therapy and motivational incentives (providing rewards to patients who remain drug-free). Continuing research may lead to new medications that help ease withdrawal symptoms, block the effects of marijuana, and prevent relapse.
Points to Remember
- Marijuana refers to the dried leaves, flowers, stems, and seeds from the Cannabis sativa or Cannabis indica plant.
- The plant contains the mind-altering chemical THC and other related compounds.
- People use marijuana by smoking, eating, drinking, or inhaling it.
- Smoking and vaping THC-rich extracts from the marijuana plant (a practice called dabbing) is on the rise.
- THC overactivates certain brain cell receptors, resulting in effects such as:
- altered senses
- changes in mood
- impaired body movement
- difficulty with thinking and problem-solving
- impaired memory and learning
- Marijuana use can have a wide range of health effects, including:
- hallucinations and paranoia
- breathing problems
- possible harm to a fetus's brain in pregnant women
- The amount of THC in marijuana has been increasing steadily in recent decades, creating more harmful effects in some people.
- It's unlikely that a person will fail a drug test or get high from passive exposure by inhaling secondhand marijuana smoke.
- There aren’t any reports of teens and adults dying from using marijuana alone, but marijuana use can cause some very uncomfortable side effects, such as anxiety and paranoia and, in rare cases, extreme psychotic reactions.
- Marijuana use can lead to a substance use disorder, which can develop into an addiction in severe cases.
- No medications are currently available to treat marijuana use disorder, but behavioral support can be effective.
Cannabis, also known as marijuana among other names,[a] is a psychoactive drug from the Cannabis plant used for medical or recreational purposes.[17][18][19] The main psychoactive part of cannabis is tetrahydrocannabinol (THC), one of 483 known compounds in the plant,[20] including at least 65 other cannabinoids.[21] Cannabis can be used by smoking, vaporizing, within food, or as an extract.[22]
Cannabis has mental and physical effects, such as creating a "high" or "stoned" feeling, a general change in perception, heightened mood, and an increase in appetite.[22][23]Onset of effects is within minutes when smoked, and about 30 to 60 minutes when cooked and eaten.[22][24] They last for between two and six hours.[24] Short-term side effects may include a decrease in short-term memory, dry mouth, impaired motor skills, red eyes, and feelings of paranoia or anxiety.[22][25][26] Long-term side effects may include addiction, decreased mental ability in those who started as teenagers, and behavioral problems in children whose mothers used cannabis during pregnancy.[22]There is a strong relation between cannabis use and the risk of psychosis,[27] though the cause-and-effect is debated.[28]
Cannabis is mostly used for recreation or as a medicinal drug, although it may also be used for spiritual purposes. In 2013, between 128 and 232 million people used cannabis (2.7% to 4.9% of the global population between the ages of 15 and 65).[29] It is the most commonly used illegal drug both in the world and the United States.[22][29] The countries with the highest use among adults as of 2018 are Zambia, the United States, Canada, and Nigeria.[30] In 2016, 51% of people in the United States had used cannabis in their lifetime.[31] About 12% had used it in the past year, and 7.3% had used it in the past month.[32]
The earliest recorded uses date from the 3rd millennium BC.[33] Since the early 20th century, cannabis has been subject to legal restrictions. The possession, use, and sale of cannabis is illegal in most countries of the world.[34][35] Medical cannabis refers to the physician-recommended use of cannabis, which takes place in Canada, Belgium, Australia, the Netherlands, Germany, Spain, and 33 U.S. states.[36][37] In September 2018, cannabis was legalized in South Africa[38] while Canada legalized recreational use of cannabis in October 2018.[39]
Contents
Uses
Medical
Medical cannabis, or medical marijuana, can refer to the use of cannabis and its cannabinoids to treat disease or improve symptoms; however, there is no single agreed-upon definition.[40][41] The rigorous scientific study of cannabis as a medicine has been hampered by production restrictions and other federal regulations.[42] There is limited evidence suggesting cannabis can be used to reduce nausea and vomiting during chemotherapy, to improve appetite in people with HIV/AIDS, and to treat chronic painand muscle spasms.[43][44][45] Its use for other medical applications is insufficient for conclusions about safety or efficacy.
Short-term use increases the risk of both minor and major adverse effects.[44] Common side effects include dizziness, feeling tired and vomiting.[44] Long-term effects of cannabis are not clear.[44] Concerns include memory and cognition problems, risk of addiction, schizophrenia in young people, and the risk of children taking it by accident.[43]
Recreational
Cannabis has psychoactive and physiological effects when consumed.[46] The immediate desired effects from consuming cannabis include relaxation and euphoria(the "high" or "stoned" feeling), a general alteration of conscious perception, increased awareness of sensation, increased libido[47] and distortions in the perception of timeand space. At higher doses, effects can include altered body image, auditory and/or visual illusions, pseudohallucinations and ataxia from selective impairment of polysynaptic reflexes. In some cases, cannabis can lead to dissociative states such as depersonalization[48][49] and derealization.[50]
Some immediate undesired side effects include a decrease in short-term memory, dry mouth, impaired motor skills and reddening of the eyes.[51] Aside from a subjective change in perception and mood, the most common short-term physical and neurological effects include increased heart rate, increased appetite and consumption of food, lowered blood pressure, impairment of short-term and working memory,[52][53]psychomotor coordination, and concentration.
Some users may experience an episode of acute psychosis, which usually abates after six hours, but in rare instances, heavy users may find the symptoms continuing for many days.[54] A reduced quality of life is associated with heavy cannabis use, although the relationship is inconsistent and weaker than for tobacco and other substances.[55] The direction of cause and effect relationship, however, is unclear.[55]
On October 17, 2018, Canada legalized cannabis for recreational adult use[56] making it the second country in the world to do so after Uruguay and the first G7 nation.[57] The Canadian Licensed Producer system may become the Gold Standard in the world for safe and secure cannabis production,[58] including provisions for a robust craft cannabis industry where many expect opportunities for experimenting with different strains.[59] Laws around use vary from province to province including age limits, retail structure, and growing at home.[56]
Spiritual
Cannabis has held sacred status in several religions. It has been used in an entheogenic context – a chemical substance used in a religious, shamanic, or spiritual context[60] - in the Indian subcontinent since the Vedic period dating back to approximately 1500 BCE, but perhaps as far back as 2000 BCE. There are several references in Greek mythology to a powerful drug that eliminated anguish and sorrow. Herodotus wrote about early ceremonial practices by the Scythians, thought to have occurred from the 5th to 2nd century BCE. In modern culture the spiritual use of cannabis has been spread by the disciples of the Rastafari movement who use cannabis as a sacrament and as an aid to meditation. The earliest known reports regarding the sacred status of cannabis in the Indian subcontinent come from the Atharva Veda estimated to have been written sometime around 2000–1400 BCE.[61]
Available forms
Cannabis is consumed in many different ways:[62]
- smoking, which typically involves burning and inhaling vaporized cannabinoids ("smoke") from small pipes, bongs (portable versions of hookahs with a water chamber), paper-wrapped jointsor tobacco-leaf-wrapped blunts, and other items.[63]
- vaporizer, which heats any form of cannabis to 165–190 °C (329–374 °F),[64] causing the active ingredients to evaporate into a vapor without burning the plant material (the boiling point of THC is 157 °C (315 °F) at atmospheric pressure).[65]
- cannabis tea, which contains relatively small concentrations of THC because THC is an oil (lipophilic) and is only slightly water-soluble (with a solubility of 2.8 mg per liter).[66] Cannabis tea is made by first adding a saturated fat to hot water (e.g. cream or any milk except skim) with a small amount of cannabis.[67]
- edibles, where cannabis is added as an ingredient to one of a variety of foods, including butter and baked goods. In India it is commonly made into a beverage, bhang.
- capsules, typically containing cannabis oil, and other dietary supplement products, for which some 220 were approved in Canada in 2018.[39]
Adverse effects
Short term
Acute effects may include anxiety and panic, impaired attention and memory, an increased risk of psychotic symptoms, [b] the inability to think clearly, and an increased risk of accidents.[70][71][72]Cannabis impaired a person's driving ability, and THC was the illicit drug most frequently found in the blood of drivers who have been involved in vehicle crashes. Those with THC in their system were from three to seven times more likely to be the cause of the accident than those who had not used either cannabis or alcohol, although its role is not necessarily causal because THC stays in the bloodstream for days to weeks after intoxication.[73][74][c]
According to the United States Department of Health and Human Services, there were 455,000 emergency room visits associated with cannabis use in 2011. These statistics include visits in which the patient was treated for a condition induced by or related to recent cannabis use. The drug use must be "implicated" in the emergency department visit, but does not need to be the direct cause of the visit. Most of the illicit drug emergency room visits involved multiple drugs.[77] In 129,000 cases, cannabis was the only implicated drug.[78][79]
The short term effects of cannabis can be altered if it has been laced with opioid drugs such as heroin or fentanyl.[80] The added drugs are meant to enhance the psychoactive properties, add to its weight, and increase profitability, despite the increased danger of overdose.[81][82][d]
Long term
Heavy, long-term exposure to marijuana may have biologically based physical, mental, behavioral and social health consequences and may be "associated with diseases of the liver (particularly with co-existing hepatitis C), lungs, heart, and vasculature".[84] It is recommended that cannabis use be stopped before and during pregnancy as it can result in negative outcomes for both the mother and baby.[85][86] However, maternal use of marijuana during pregnancy does not appear to be associated with low birth weight or early delivery after controlling for tobacco use and other confounding factors.[87] A 2014 review found that while cannabis use may be less harmful than alcohol use, the recommendation to substitute it for problematic drinking was premature without further study.[88] Various surveys conducted between 2015 and 2019 found that many users of cannabis substitute it for prescription drugs (including opioids), alcohol, and tobacco; most of those who used it in place of alcohol or tobacco either reduced or stopped their intake of the latter substances.[89]
A limited number of studies have examined the effects of cannabis smoking on the respiratory system.[90] Chronic heavy marijuana smoking is associated with coughing, production of sputum, wheezing, and other symptoms of chronic bronchitis.[70] The available evidence does not support a causal relationship between cannabis use and chronic obstructive pulmonary disease.[91] Short-term use of cannabis is associated with bronchodilation.[92] Other side effects of cannabis use include cannabinoid hyperemesis syndrome.[93]
Cannabis smoke contains thousands of organic and inorganic chemical compounds. This tar is chemically similar to that found in tobacco smoke,[94] and over fifty known carcinogens have been identified in cannabis smoke,[95] including; nitrosamines, reactive aldehydes, and polycylic hydrocarbons, including benz[a]pyrene.[96] Cannabis smoke is also inhaled more deeply than is tobacco smoke.[97] As of 2015, there is no consensus regarding whether cannabis smoking is associated with an increased risk of cancer.[98] Light and moderate use of cannabis is not believed to increase risk of lung or upper airway cancer. Evidence for causing these cancers is mixed concerning heavy, long-term use. In general there are far lower risks of pulmonary complications for regular cannabis smokers when compared with those of tobacco.[99] A 2015 review found an association between cannabis use and the development of testicular germ cell tumors (TGCTs), particularly non-seminoma TGCTs.[100] A 2015 analysis of six studies found little evidence that long-term or regular cannabis smoking was associated with lung cancer risk, though it could not rule out whether an association with heavy smoking exists.[101] Another 2015 meta-analysis found no association between lifetime cannabis use and risk of head or neck cancer.[102] Combustion products are not present when using a vaporizer, consuming THC in pill form, or consuming cannabis foods.[103]
There is concern that cannabis may contribute to cardiovascular disease,[104] but as of 2018, evidence of this relationship was unclear.[105][106] Cannabis is believed to be an aggravating factor in rare cases of arteritis, a serious condition that in some cases leads to amputation. Because 97% of case-reports also smoked tobacco, a formal association with cannabis could not be made. If cannabis arteritis turns out to be a distinct clinical entity, it might be the consequence of vasoconstrictor activity observed from delta-8-THC and delta-9-THC.[107] Other serious cardiovascular events including myocardial infarction, stroke,[108] sudden cardiac death, and cardiomyopathy have been reported to be temporally associated with cannabis use. Research in these events is complicated because cannabis is often used in conjunction with tobacco, and drugs such as alcohol and cocaine.[109] These putative effects can be taken in context of a wide range of cardiovascular phenomena regulated by the endocannabinoid system and an overall role of cannabis in causing decreased peripheral resistance and increased cardiac output, which potentially could pose a threat to those with cardiovascular disease.[110] There is some evidence from case reports that cannabis use may provoke fatal cardiovascular events in young people who have not been diagnosed with cardiovascular disease.[111] Smoking cannabis has also been shown to increase the risk of myocardial infarction by 4.8 times for the 60 minutes after consumption.[112]
Neuroimaging
Although global abnormalities in white matter and grey matter are not associated with cannabis abuse, reduced hippocampal volume is consistently found. Amygdalar abnormalities are sometimes reported, although findings are inconsistent.[113][114][115] Preliminary evidence suggests that this effect is largely mediated by THC, and that CBD may even have a protective effect.[116]
Cannabis use is associated with increased recruitment of task-related areas, such as the dorsolateral prefrontal cortex, which is thought to reflect compensatory activity due to reduced processing efficiency.[115][114][117] Cannabis use is also associated with downregulation of CB1 receptors. The magnitude of down regulation is associated with cumulative cannabis exposure, and is reversed after one month of abstinence.[118][119][120] There is limited evidence that chronic cannabis use can reduce levels of glutamate metabolites in the human brain.[121]
Cognition
A 2015 meta analysis found that, although a longer period of abstinence was associated with smaller magnitudes of impairment, both retrospective and prospective memory were impaired in cannabis users. The authors concluded that some, but not all, of the deficits associated with cannabis use were reversible.[122] A 2012 meta analyses found that deficits in most domains of cognition persisted beyond the acute period of intoxication, but was not evident in studies where subjects were abstinent for more than 25 days.[123] Few high quality studies have been performed on the long-term effects of cannabis on cognition, and results were generally inconsistent.[124]Furthermore, effect sizes of significant findings were generally small.[123] One review concluded that, although most cognitive faculties were unimpaired by cannabis use, residual deficits occurred in executive functions.[125] Impairments in executive functioning are most consistently found in older populations, which may reflect heavier cannabis exposure, or developmental effects associated with adolescent cannabis use.[126] One review found three prospective cohort studies that examined the relationship between self reported cannabis use and intelligence quotient (IQ). The study following the largest number of heavy cannabis users reported that IQ declined between ages 7–13 and age 38. Poorer school performance and increased incidence of leaving school early were both associated with cannabis use, although a causal relationship was not established.[118] Cannabis users demonstrated increased activity in task-related brain regions, consistent with reduced processing efficiency.[127]
Psychiatric
At an epidemiological level, a dose–response relationship exists between cannabis use and increased risk of psychosis[128][129][130] and earlier onset of psychosis.[131] Although the epidemiological association is robust, evidence to prove a causal relationship is lacking.[132]But a biological causal pathway is plausible, especially if there is a genetic predisposition to mental illness, in which case cannabis may be a trigger.[133][better source needed]
It is not clear whether cannabis use affects the rate of suicide.[134][135] Cannabis may also increase the risk of depression, but insufficient research has been performed to draw a conclusion.[136][129] Cannabis use is associated with increased risk of anxiety disorders, although causality has not been established.[137]
A February 2019 review found that cannabis use during adolescence was associated with an increased risk of developing depression and suicidal behavior later in life, while finding no effect on anxiety.[138]
Reinforcement disorders
About 9% of those who experiment with marijuana eventually become dependent according to DSM-IV (1994) criteria.[79] A 2013 review estimates daily use is associated with a 10-20% rate of dependence.[43] The highest risk of cannabis dependence is found in those with a history of poor academic achievement, deviant behavior in childhood and adolescence, rebelliousness, poor parental relationships, or a parental history of drug and alcohol problems.[139] Of daily users, about 50% experience withdrawal upon cessation of use (i.e. are dependent), characterized by sleep problems, irritability, dysphoria, and craving.[118] Cannabis withdrawal is less severe than withdrawal from alcohol.[140]
According to DSM-V criteria, 9% of those who are exposed to cannabis develop cannabis use disorder, compared to 20% for cocaine, 23% for alcohol and 68% for nicotine. Cannabis abuse disorder in the DSM-V involves a combination of DSM-IV criteria for cannabis abuse and dependence, plus the addition of craving, minus the criterion related to legal troubles.[118]
Overdose
THC, the principal psychoactive constituent of the cannabis plant, has low toxicity. The dose of THC needed to kill 50% of tested rodents is extremely high. Cannabis has not been reported to cause fatal overdose in humans.[134]
Pharmacology
Mechanism of action
The high lipid-solubility of cannabinoids results in their persisting in the body for long periods of time.[141] Even after a single administration of THC, detectable levels of THC can be found in the body for weeks or longer (depending on the amount administered and the sensitivity of the assessment method).[141] A number of investigators have suggested that this is an important factor in marijuana's effects, perhaps because cannabinoids may accumulate in the body, particularly in the lipid membranes of neurons.[142]
Not until the end of the 20th century was the specific mechanism of action of THC at the neuronal level studied.[citation needed]Researchers have subsequently confirmed that THC exerts its most prominent effects via its actions on two types of cannabinoid receptors, the CB1 receptor and the CB2 receptor, both of which are G protein-coupled receptors.[143] The CB1 receptor is found primarily in the brain as well as in some peripheral tissues, and the CB2 receptor is found primarily in peripheral tissues, but is also expressed in neuroglial cells.[144] THC appears to alter mood and cognition through its agonist actions on the CB1 receptors, which inhibit a secondary messenger system (adenylate cyclase) in a dose-dependent manner. These actions can be blocked by the selective CB1 receptor antagonist rimonabant (SR141716), which has been shown in clinical trials to be an effective treatment for smoking cessation, weight loss, and as a means of controlling or reducing metabolic syndrome risk factors.[145] However, due to the dysphoric effect of CB1receptor antagonists, this drug is often discontinued due to these side effects.[146]
Via CB1 receptor activation, THC indirectly increases dopamine release and produces psychotropic effects.[147] Cannabidiol (CBD) also acts as an allosteric modulator of the μ- and δ-opioid receptors.[148] THC also potentiates the effects of the glycine receptors.[149] It is unknown if or how these actions contribute to the effects of cannabis.[150]
Chemistry
Detection in body fluids
THC and its major (inactive) metabolite, THC-COOH, can be measured in blood, urine, hair, oral fluid or sweat using chromatographictechniques as part of a drug use testing program or a forensic investigation of a traffic or other criminal offense.[54] The concentrations obtained from such analyses can often be helpful in distinguishing active use from passive exposure, elapsed time since use, and extent or duration of use. These tests cannot, however, distinguish authorized cannabis smoking for medical purposes from unauthorized recreational smoking.[151] Commercial cannabinoid immunoassays, often employed as the initial screening method when testing physiological specimens for marijuana presence, have different degrees of cross-reactivity with THC and its metabolites.[152] Urine contains predominantly THC-COOH, while hair, oral fluid and sweat contain primarily THC.[54] Blood may contain both substances, with the relative amounts dependent on the recency and extent of usage.[54]
The Duquenois–Levine test is commonly used as a screening test in the field, but it cannot definitively confirm the presence of cannabis, as a large range of substances have been shown to give false positives.[153] Despite this, it is common in the United States for prosecutors to seek plea bargains on the basis of positive D–L tests, claiming them to be conclusive, or even to seek conviction without the use of gas chromatography confirmation, which can only be done in the lab.[154] In 2011, researchers at John Jay College of Criminal Justice reported that dietary zinc supplements can mask the presence of THC and other drugs in urine.[155] However, a 2013 study conducted by researchers at the University of Utah School of Medicine refute the possibility of self-administered zinc producing false-negative urine drug tests.[156]
Varieties and strains
CBD is a 5-HT1A receptor agonist, which may also contribute to an anxiolytic effect.[157] This likely means the high concentrations of CBD found in Cannabis indica mitigate the anxiogenic effect of THC significantly.[157] The cannabis industry claims that sativa strains provide a more stimulating psychoactive high while indica strains are more sedating with a body high.[158] However this is disputed by researchers.[159]
Psychoactive ingredients
According to the United Nations Office on Drugs and Crime (UNODC), "the amount of THC present in a cannabis sample is generally used as a measure of cannabis potency."[160] The three main forms of cannabis products are the flower, resin (hashish), and oil (hash oil). The UNODC states that cannabis often contains 5% THC content, resin "can contain up to 20% THC content", and that "Cannabis oil may contain more than 60% THC content."[160]
A 2012 review found that the THC content in marijuana had increased worldwide from 1970 to 2009.[161] It is unclear, however, whether the increase in THC content has caused people to consume more THC or if users adjust based on the potency of the cannabis. It is likely that the higher THC content allows people to ingest less tar. At the same time, CBD levels in seized samples have lowered, in part because of the desire to produce higher THC levels and because more illegal growers cultivate indoors using artificial lights. This helps avoid detection but reduces the CBD production of the plant.[162]
Australia's National Cannabis Prevention and Information Centre (NCPIC) states that the buds (flowers) of the female cannabis plant contain the highest concentration of THC, followed by the leaves. The stalks and seeds have "much lower THC levels".[163] The UN states that leaves can contain ten times less THC than the buds, and the stalks one hundred times less THC.[160]
After revisions to cannabis scheduling in the UK, the government moved cannabis back from a class C to a class B drug. A purported reason was the appearance of high potency cannabis. They believe skunk accounts for between 70 and 80% of samples seized by police[164] (despite the fact that skunk can sometimes be incorrectly mistaken for all types of herbal cannabis).[165][166] Extracts such as hashish and hash oil typically contain more THC than high potency cannabis flowers.[167]
Preparations
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Marijuana
Marijuana or marihuana (herbal cannabis),[19] consists of the dried flowers and subtending leaves and stems of the female Cannabisplant.[168][169][170][171] This is the most widely consumed form,[171] containing 3% to 20% THC,[172] with reports of up-to 33% THC.[173]This is the stock material from which all other preparations are derived. Although herbal cannabis and industrial hemp derive from the same species and contain the psychoactive component (THC), they are distinct strains with unique biochemical compositions and uses. Hemp has lower concentrations of THC and higher concentrations of CBD, which decreases the psychoactive effects[174][175]
Kief
Kief is a powder, rich in trichomes,[176] which can be sifted from the leaves and flowers of cannabis plants and either consumed in powder form or compressed to produce cakes of hashish.[177] The word "kif" derives from colloquial Arabic كيف kēf/kīf, meaning pleasure.[178]
Hashish
Hashish (also spelled hasheesh, hashisha, or simply hash) is a concentrated resin cake or ball produced from pressed kief, the detached trichomes and fine material that falls off cannabis flowers and leaves.[179] or from scraping the resin from the surface of the plants and rolling it into balls. It varies in color from black to golden brown depending upon purity and variety of cultivar it was obtained from.[180] It can be consumed orally or smoked, and is also vaporised, or 'vaped'.[181] The term "rosin hash" refers to a high quality solventless product obtained through heat and pressure.[182]
Tincture
Cannabinoids can be extracted from cannabis plant matter using high-proof spirits (often grain alcohol) to create a tincture, often referred to as "green dragon".[183] Nabiximols is a branded product name from a tincture manufacturing pharmaceutical company.[184]
Hash oil
Hash oil is a resinous matrix of cannabinoids obtained from the Cannabis plant by solvent extraction,[185] formed into a hardened or viscous mass.[186] Hash oil can be the most potent of the main cannabis products because of its high level of psychoactive compound per its volume, which can vary depending on the plant's mix of essential oils and psychoactive compounds.[187] Butane and supercriticalcarbon dioxide hash oil have become popular in recent years.[188]
Infusions
There are many varieties of cannabis infusions owing to the variety of non-volatile solvents used.[189] The plant material is mixed with the solvent and then pressed and filtered to express the oils of the plant into the solvent. Examples of solvents used in this process are cocoa butter, dairy butter, cooking oil, glycerine, and skin moisturizers. Depending on the solvent, these may be used in cannabis foods or applied topically.[190]
Medical use
Medical marijuana refers to the use of the Cannabis plant as a physician-recommended herbal therapy as well as synthetic[191] THC and cannabinoids. So far, the medical use of cannabis is legal only in a limited number of territories, including Canada,[39] Belgium, Australia, the Netherlands, Spain, and many U.S. states. This usage generally requires a prescription, and distribution is usually done within a framework defined by local laws. There is evidence supporting the use of cannabis or its derivatives in the treatment of chemotherapy-induced nausea and vomiting, neuropathic pain, and multiple sclerosis. Lower levels of evidence support its use for AIDS wasting syndrome, epilepsy, rheumatoid arthritis, and glaucoma.[79]
History
Cannabis is indigenous to Central Asia[192] and the Indian subcontinent,[193] and its use for fabric and rope dates back to the Neolithic age in China and Japan.[194][195] It is unclear when cannabis first became known for its psychoactive properties; some scholars suggest that the ancient Indian drug soma, mentioned in the Vedas, was cannabis, although this theory is disputed.[196]
Cannabis was known to the ancient Assyrians, who discovered its psychoactive properties through the Iranians.[197] Using it in some religious ceremonies, they called it qunubu (meaning "way to produce smoke"), a probable origin of the modern word "cannabis".[198] The Iranians also introduced cannabis to the Scythians, Thracians and Dacians, whose shamans (the kapnobatai—"those who walk on smoke/clouds") burned cannabis flowers to induce trance.[199] The plant was used in China before 2800 BC, and found therapeutic use in India by 1000 BC, where it was used in food and drink, including bhang.[200][201]
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Cannabis has an ancient history of ritual use and is found in pharmacological cults around the world. Hemp seeds discovered by archaeologists at Pazyryk suggest early ceremonial practices like eating by the Scythians occurred during the 5th to 2nd century BC, confirming previous historical reports by Herodotus.[202] It was used by Muslims in various Sufi orders as early as the Mamluk period, for example by the Qalandars.[203] Smoking pipes uncovered in Ethiopia and carbon-dated to around c. AD 1320 were found to have traces of cannabis.[204]
Following an 1836–1840 travel in North Africa and the Middle East, French physician Jacques-Joseph Moreau wrote on the psychological effects of cannabis use; he was a member of Paris' Club des Hashischins.[citation needed] In 1842, Irish physician William Brooke O'Shaughnessy, who had studied the drug while working as a medical officer in Bengal with the East India company, brought a quantity of cannabis with him on his return to Britain, provoking renewed interest in the West.[205] Examples of classic literature of the period featuring cannabis include Les paradis artificiels(1860) by Charles Baudelaire and The Hasheesh Eater (1857) by Fitz Hugh Ludlow.
Cannabis was criminalized in various countries beginning in the 19th century. The British colonies of Mauritius banned cannabis in 1840 over concerns on its effect on Indian indentured workers;[206] the same occurred in British Singapore in 1870.[207] In the United States, the first restrictions on sale of cannabis came in 1906 (in District of Columbia).[208] It was outlawed in Jamaica (then a British colony) in 1913, in South Africa in 1922, and in the United Kingdom and New Zealand in the 1920s.[209] Canada criminalized cannabis in The Opium and Narcotic Drug Act, 1923,[210] before any reports of the use of the drug in Canada, but eventually legalized its consumption for recreational and medicinal purposes in 2018.[39]
In 1925, a compromise was made at an international conference in The Hague about the International Opium Convention that banned exportation of "Indian hemp" to countries that had prohibited its use, and requiring importing countries to issue certificates approving the importation and stating that the shipment was required "exclusively for medical or scientific purposes". It also required parties to "exercise an effective control of such a nature as to prevent the illicit international traffic in Indian hemp and especially in the resin".[211][212] In the United States in 1937, the Marihuana Tax Act was passed,[213] and prohibited the production of hemp in addition to cannabis.
In 1972, the Dutch government divided drugs into more- and less-dangerous categories, with cannabis being in the lesser category. Accordingly, possession of 30 grams or less was made a misdemeanor.[214] Cannabis has been available for recreational use in coffee shops since 1976.[215] Cannabis products are only sold openly in certain local "coffeeshops" and possession of up to 5 grams for personal use is decriminalised, however: the police may still confiscate it, which often happens in car checks near the border. Other types of sales and transportation are not permitted, although the general approach toward cannabis was lenient even before official decriminalisation.[216][217][218]
In Uruguay, President Jose Mujica signed legislation to legalize recreational cannabis in December 2013, making Uruguay the first country in the modern era to legalize cannabis. In August 2014, Uruguay legalized growing up to six plants at home, as well as the formation of growing clubs, and a state-controlled marijuana dispensary regime.
As of October 17, 2018 when recreational use of cannabis was legalized in Canada, dietary supplements for human use and veterinary health products containing not more than 10 parts per million of THC extract were approved for marketing; Nabiximols (as Sativex) is used as a prescription drug in Canada.[39]
The United Nations' World Drug Report stated that cannabis "was the world's most widely produced, trafficked, and consumed drug in the world in 2010", and estimated between 128 million and 238 million users globally in 2015.[219][220]
Society and culture
Legal status
Since the beginning of the 20th century, most countries have enacted lawsagainst the cultivation, possession or transfer of cannabis.[221] These laws have impacted adversely on cannabis cultivation for non-recreational purposes, but there are many regions where handling of cannabis is legal or licensed. Many jurisdictions have lessened the penalties for possession of small quantities of cannabis so that it is punished by confiscation and sometimes a fine, rather than imprisonment, focusing more on those who traffic the drug on the black market.
In some areas where cannabis use had been historically tolerated, new restrictions were instituted, such as the closing of cannabis coffee shops near the borders of the Netherlands,[222] and closing of coffee shops near secondary schools in the Netherlands.[223] In Copenhagen, Denmark in 2014, mayor Frank Jensen discussed possibilities for the city to legalize cannabis production and commerce.[224]
Some jurisdictions use free voluntary treatment programs and/or mandatory treatment programs for frequent known users. Simple possession can carry long prison terms in some countries, particularly in East Asia, where the sale of cannabis may lead to a sentence of life in prison or even execution. Political parties, non-profit organizations, and causes based on the legalization of medical cannabis and/or legalizing the plant entirely (with some restrictions) have emerged in such countries as China and Thailand.[225][226]
In December 2012, the U.S. state of Washington became the first state to officially legalize cannabis in a state law (Washington Initiative 502) (but still illegal by federal law),[227] with the state of Colorado following close behind (Colorado Amendment 64).[228] On January 1, 2013, the first marijuana "club" for private marijuana smoking (no buying or selling, however) was allowed for the first time in Colorado.[229] The California Supreme Court decided in May 2013 that local governments can ban medical marijuana dispensaries despite a state law in California that permits the use of cannabis for medical purposes. At least 180 cities across California have enacted bans in recent years.[230]
In December 2013, Uruguay became the first country to legalize growing, sale and use of cannabis.[231] After a long delay in implementing the retail component of the law, in 2017 sixteen pharmacies were authorized to sell cannabis commercially.[232] On June 19, 2018, the Canadian Senate passed a bill and the Prime Minister announced the effective legalization date as October 17, 2018.[39][233]Canada is the second nation to legalize the drug.[234]
In November 2015, Uttarakhand became the first state of India to legalize the cultivation of hemp for industrial purposes.[235] Usage within the Hindu and Buddhist cultures of the Indian subcontinent is common, with many street vendors in India openly selling products infused with cannabis, and traditional medical practitioners in Sri Lanka selling products infused with cannabis for recreational purposes and well as for religious celebrations.[236] It was criminalized in the Indian subcontinent by the Dutch and then the British. India and Sri Lanka have allowed cannabis to be taken in the context of traditional culture for recreational/celebratory purposes and also for medicinal purposes.[236]
On October 17, 2015, Australian health minister Sussan Ley presented a new law that will allow the cultivation of cannabis for scientific research and medical trials on patients.[237]
As the drug has increasingly come to be seen as a health issue instead of criminal behavior, marijuana has also been legalized or decriminalized in: Czech Republic,[238] Colombia,[239][240] Ecuador,[241][242][243] Mexico,[244][245] Portugal,[246] South Africa[247] and Canada.[39]
Usage
In 2013, between 128 and 232 million people used cannabis (2.7% to 4.9% of the global population between the ages of 15 and 65).[29]Cannabis is by far the most widely used illicit substance.[249]
United States
Between 1973 and 1978, eleven states decriminalized marijuana.[250] In 2001, Nevada reduced marijuana possession to a misdemeanor and since 2012, several other states have decriminalized and even legalized marijuana.[250]
In 2015, almost half of the people in the United States had tried marijuana, 12% had used it in the past year, and 7.3% had used it in the past month.[32] In 2014, daily marijuana use amongst US college students had reached its highest level since records began in 1980, rising from 3.5% in 2007 to 5.9% in 2014 and had surpassed daily cigarette use.[251]
In the US, men are over twice as likely to use marijuana as women and 18-29 year-olds are six times more likely to use as over 65-year-olds.[252] In 2015, a record 44% of the US population has tried marijuana in their lifetime, an increase from 38% in 2013 and 33% in 1985.[252]
Marijuana use in the United States is three times above the global average, but in line with other Western democracies. 44% of American 12th graders have tried the drug at least once, and the typical age of first-use is 16, similar to the typical age of first-use for alcohol but lower than the first-use age for other illicit drugs.[249]
Economics
Production
It is often claimed by growers and breeders of herbal cannabis that advances in breeding and cultivation techniques have increased the potency of cannabis since the late 1960s and early '70s when THC was first discovered and understood. However, potent seedless cannabis such as "Thai sticks" were already available at that time. Sinsemilla (Spanish for "without seed") is the dried, seedless inflorescences of female cannabis plants. Because THC production drops off once pollination occurs, the male plants (which produce little THC themselves) are eliminated before they shed pollen to prevent pollination. Advanced cultivation techniques such as hydroponics, cloning, high-intensity artificial lighting, and the sea of green method are frequently employed as a response (in part) to prohibition enforcement efforts that make outdoor cultivation more risky. It is often cited that the average levels of THC in cannabis sold in the United States rose dramatically between the 1970s and 2000, but such statements are likely skewed because undue weight is given to much more expensive and potent, but less prevalent samples.[253]
"Skunk" refers to several named strains of potent cannabis, grown through selective breeding and sometimes hydroponics. It is a cross-breed of Cannabis sativa and C. indica (although other strains of this mix exist in abundance). Skunk cannabis potency ranges usually from 6% to 15% and rarely as high as 20%. The average THC level in coffee shops in the Netherlands is about 18–19%.[254]
Price
The price or street value of cannabis varies widely depending on geographic area and potency.[255]
In the United States, cannabis is overall the number four value crop, and is number one or two in many states including California, New York and Florida, averaging $3,000 per pound ($6,600/kg).[256][257] Some believe it generates an estimated $36 billion market.[258]Some have argued that this estimate is methodologically flawed, and makes unrealistic assumptions about the level of marijuana consumption. Other estimates claiming to correct for this flaw claim that the market is between $2.1-$4.3 billion.[249] The United Nations Office on Drugs and Crime claims in its 2008 World Drug Report that typical U.S. retail prices are $10–15 per gram (approximately $280–420 per ounce). Street prices in North America are known to range from about $40–$400 per ounce ($1.4–$14/g), depending on quality.[259]
The European Monitoring Centre for Drugs and Drug Addiction reports that typical retail prices in Europe for cannabis varies from €2 to €20 per gram, with a majority of European countries reporting prices in the range €4–10.[260]
Gateway drug
The Gateway Hypothesis states that cannabis use increases the probability of trying "harder" drugs. The hypothesis has been hotly debated as it is regarded by some as the primary rationale for the United States prohibition on cannabis use.[261][262] A Pew Research Center poll found that political opposition to marijuana use was significantly associated with concerns about health effects and whether legalization would increase marijuana use by children.[263]
Some studies state that while there is no proof for the gateway hypothesis,[264] young cannabis users should still be considered as a risk group for intervention programs.[265] Other findings indicate that hard drug users are likely to be poly-drug users, and that interventions must address the use of multiple drugs instead of a single hard drug.[266] Almost two-thirds of the poly drug users in the "2009/10 Scottish Crime and Justice Survey" used cannabis.[267]
The gateway effect may appear due to social factors involved in using any illegal drug. Because of the illegal status of cannabis, its consumers are likely to find themselves in situations allowing them to acquaint with individuals using or selling other illegal drugs.[268][269] Utilizing this argument some studies have shown that alcohol and tobacco may additionally be regarded as gateway drugs;[270] however, a more parsimonious explanation could be that cannabis is simply more readily available (and at an earlier age) than illegal hard drugs. In turn alcohol and tobacco are easier to obtain at an earlier point than is cannabis (though the reverse may be true in some areas), thus leading to the "gateway sequence" in those individuals since they are most likely to experiment with any drug offered.[261]
An alternative to the gateway hypothesis is the common liability to addiction (CLA) theory. It states that some individuals are, for various reasons, willing to try multiple recreational substances. The "gateway" drugs are merely those that are (usually) available at an earlier age than the harder drugs. Researchers have noted in an extensive review that it is dangerous to present the sequence of events described in gateway "theory" in causative terms as this hinders both research and intervention.[271]
Research
Cannabis research is challenging since the plant is illegal in most countries.[272][273][274][275][276] Research-grade samples of the drug are difficult to obtain for research purposes, unless granted under authority of national governments.
There are also other difficulties in researching the effects of cannabis. Many people who smoke cannabis also smoke tobacco.[277] This causes confounding factors, where questions arise as to whether the tobacco, the cannabis, or both that have caused a cancer. Another difficulty researchers have is in recruiting people who smoke cannabis into studies. Because cannabis is an illegal drug in many countries, people may be reluctant to take part in research, and if they do agree to take part, they may not say how much cannabis they actually smoke.[278]
A 2015 review found that the use of high CBD-to-THC strains of cannabis showed significantly fewer positive symptoms such as delusions and hallucinations, better cognitive function and both lower risk for developing psychosis, as well as a later age of onset of the illness, compared to cannabis with low CBD-to-THC ratios.[279] A 2014 Cochrane review found that research was insufficient to determine the safety and efficacy to using cannabis to treat schizophrenia or psychosis.[280] As of 2017, the molecular mechanisms for the anti-inflammatory and possible pain relieving effects of cannabis are under preliminary research.[281]
By country
Canada
As of October 2018 when recreational use of cannabis was legalized in Canada, some 220 dietary supplements and 19 veterinary health products containing not more than 10 parts per million of THC extract were approved with general health claims for treating minor conditions.[39]
United States
Cannabis use started to become popular in the United States in the 1970s.[252] Support for legalization has increased in the United States and several U.S. states have legalized recreational or medical use.[282] A 2018 Social Science Research study found that the main determinants of such changes in attitudes toward marijuana regulation since the 1990s were changes in media framing of marijuana, a decline in perception of the riskiness of marijuana, a decline in overall punitiveness, and a decrease in religious affiliation. [283]
South Africa
Private use of cannabis was legalized in September 2018 after a unanimous decision by the Constitutional Court in Johannesburg.[284]South Africa is the world's third largest producer of cannabis,[285] and the plant has historically been used by traditional healers[286] and Rastafari.[287]
Ref:https://en.wikipedia.org/wiki/Cannabis_(drug)
Tetrahydrocannabinol (THC) is one of at least 113 cannabinoids identified in cannabis. THC is the principal psychoactive constituent of cannabis. With chemical name (−)-trans-Δ⁹-tetrahydrocannabinol, the term THC also refers to cannabinoid isomers.
Like most pharmacologically-active secondary metabolites of plants, THC is a lipidfound in cannabis,[9] assumed to be involved in the plant's self-defense, putatively against insect predation, ultraviolet light, and environmental stress.[10][11][12]
THC, along with its double bond isomers and their stereoisomers, is one of only three cannabinoids scheduled by the UN Convention on Psychotropic Substances (the other two are dimethylheptylpyran and parahexyl). It was listed under Schedule I in 1971, but reclassified to Schedule II in 1991 following a recommendation from the WHO. Based on subsequent studies, the WHO has recommended the reclassification to the less-stringent Schedule III.[13] Cannabis as a plant is scheduled by the Single Convention on Narcotic Drugs (Schedule I and IV). It is specifically still listed under Schedule I by US federal law[14] under the Controlled Substances Act for having "no accepted medical use" and "lack of accepted safety". However, dronabinol is a synthetic form of THC approved by the FDA as an appetite stimulant for people with AIDS and antiemetic for people receiving chemotherapy.[15] The pharmaceutical formulation dronabinol is an oily resin provided in capsules available by prescription in the United States, Canada, Germany, and New Zealand.
Contents
Medical uses
THC is an active ingredient in Nabiximols, a specific extract of Cannabis that was approved as a botanical drug in the United Kingdom in 2010 as a mouth spray for people with multiple sclerosis to alleviate neuropathic pain, spasticity, overactive bladder, and other symptoms.[16][17] Nabiximols (as Sativex) is available as a prescription drug in Canada.[18]
Pharmacology
Mechanism of action
The actions of THC result from its partial agonist activity at the cannabinoid receptorCB1 (Ki = 10 nM[19]), located mainly in the central nervous system, and the CB2 receptor (Ki = 24 nM[19]), mainly expressed in cells of the immune system.[20] The psychoactive effects of THC are primarily mediated by the activation of cannabinoid receptors, which result in a decrease in the concentration of the second messenger molecule cAMPthrough inhibition of adenylate cyclase.[21]
The presence of these specialized cannabinoid receptors in the brain led researchers to the discovery of endocannabinoids, such as anandamide and 2-arachidonoyl glyceride (2-AG). THC targets receptors in a manner far less selective than endocannabinoid molecules released during retrograde signaling, as the drug has a relatively low cannabinoid receptor efficacy and affinity. In populations of low cannabinoid receptor density, THC may act to antagonize endogenous agonists that possess greater receptor efficacy.[22] THC is a lipophilic molecule[23] and may bind non-specifically to a variety of entities in the brain and body, such as adipose tissue (fat).[24][25]
THC, similarly to cannabidiol, albeit less potently, is a positive allosteric modulator of the μ- and δ-opioid receptors.[26]
Due to its partial agonistic activity, THC appears to result in greater downregulation of cannabinoid receptors than endocannabinoids, further limiting its efficacy over other cannabinoids. While tolerance may limit the maximal effects of certain drugs, evidence suggests that tolerance develops irregularly for different effects with greater resistance for primary over side-effects, and may actually serve to enhance the drug's therapeutic window.[22] However, this form of tolerance appears to be irregular throughout mouse brain areas. THC, as well as other cannabinoids that contain a phenol group, possesses mild activity sufficient to protect neurons against oxidative stress, such as that produced by glutamate-induced excitotoxicity.[20]
Pharmacokinetics
THC is metabolized mainly to 11-OH-THC by the body. This metabolite is still psychoactive and is further oxidized to 11-nor-9-carboxy-THC (THC-COOH). In humans and animals, more than 100 metabolites could be identified, but 11-OH-THC and THC-COOH are the dominating metabolites.[27] Metabolism occurs mainly in the liver by cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP3A4.[28] More than 55% of THC is excreted in the feces and ≈20% in the urine. The main metabolite in urine is the ester of glucuronic acid and THC-COOH and free THC-COOH. In the feces, mainly 11-OH-THC was detected.[29]
Physical and chemical properties
Discovery and structure identification
In 1940, cannabidiol was isolated and identified from Cannabis sativa,[30] and THC was isolated and described for its structure and synthesis in 1964.[31][32]
Solubility
As with many aromatic terpenoids, THC has a very low solubility in water, but good solubility in most organic solvents, specifically lipids and alcohols.[6]
Total synthesis
A total synthesis of the compound was reported in 1965; that procedure called for the intramolecular alkyl lithium attack on a starting carbonyl to form the fused rings, and a tosyl chloride mediated formation of the ether.[33][third-party source needed]
Biosynthesis
In the Cannabis plant, THC occurs mainly as tetrahydrocannabinolic acid (THCA, 2-COOH-THC, THC-COOH). Geranyl pyrophosphate and olivetolic acid react, catalysed by an enzyme to produce cannabigerolic acid,[34] which is cyclized by the enzyme THC acid synthase to give THCA. Over time, or when heated, THCA is decarboxylated, producing THC. The pathway for THCA biosynthesis is similar to that which produces the bitter acid humulone in hops.[35][36]
Detection in body fluids
THC and its 11-OH-THC and THC-COOH metabolites can be detected and quantified in blood, urine, hair, oral fluid or sweat using a combination of immunoassay and chromatographictechniques as part of a drug use testing program or in a forensic investigation.[37][38][39]
History
THC was first isolated in 1964 by Raphael Mechoulam and Yechiel Gaoni at the Weizmann Institute of Science in Israel.[31][40][41]
At its 33rd meeting, in 2003, the World Health Organization Expert Committee on Drug Dependence recommended transferring THC to Schedule IV of the Convention, citing its medical uses and low abuse potential.[42]
Society and culture
Comparisons with medical cannabis
Female cannabis plants contain at least 113 cannabinoids,[43] including cannabidiol (CBD), thought to be the major anticonvulsant that helps people with multiple sclerosis;[44] and cannabichromene (CBC), an anti-inflammatory which may contribute to the pain-killingeffect of cannabis.[45]
Regulation in Canada
As of October 2018 when recreational use of cannabis was legalized in Canada, some 220 dietary supplements and 19 veterinary health products containing not more than 10 parts per million of THC extract were approved with general health claims for treating minor conditions.[18]
Research
The status of THC as an illegal drug in most countries imposes restrictions on research material supply and funding, such as in the United States where the National Institute on Drug Abuse and Drug Enforcement Administration regulated sources of cannabis for researchers until August 2016 when licenses were provided to growers for supplies of medical marijuana.[46] Although cannabis is legalized for medical uses in half of the United States, no products have been approved for federal commerce by the Food and Drug Administration, a status that limits cultivation, manufacture, distribution, clinical research, and therapeutic applications.[47]
In April 2014, the American Academy of Neurology found evidence supporting the effectiveness of the cannabis extracts in treating certain symptoms of multiple sclerosis and pain, but there was insufficient evidence to determine effectiveness for treating several other neurological diseases.[48] A 2015 review confirmed that medical marijuana was effective for treating spasticity and chronic pain, but caused numerous short-lasting adverse events, such as euphoria and dizziness.[49]
Multiple sclerosis symptoms
- Spasticity. Based on the results of 3 high quality trials and 5 of lower quality, oral cannabis extract was rated as effective, and THC as probably effective, for improving people's subjective experience of spasticity. Oral cannabis extract and THC both were rated as possibly effective for improving objective measures of spasticity.[48][49]
- Centrally mediated pain and painful spasms. Based on the results of 4 high quality trials and 4 low quality trials, oral cannabis extract was rated as effective, and THC as probably effective in treating central pain and painful spasms.[48]
- Bladder dysfunction. Based on a single high quality study, oral cannabis extract and THC were rated as probably ineffective for controlling bladder complaints in multiple sclerosis[48]
Neurodegenerative disorders
- Huntington disease. No reliable conclusions could be drawn regarding the effectiveness of THC or oral cannabis extract in treating the symptoms of Huntington disease as the available trials were too small to reliably detect any difference[48]
- Parkinson's disease. Based on a single study, oral CBD extract was rated probably ineffective in treating levodopa-induced dyskinesia in Parkinson's disease.[48]
- Alzheimer's disease. A 2011 Cochrane Review found insufficient evidence to conclude whether cannabis products have any utility in the treatment of Alzheimer's disease.[50]
Other neurological disorders
- Tourette syndrome. The available data was determined to be insufficient to allow reliable conclusions to be drawn regarding the effectiveness of oral cannabis extract or THC in controlling tics.[48]
- Cervical dystonia. Insufficient data was available to assess the effectiveness of oral cannabis extract of THC in treating cervical dystonia.[48]
- Epilepsy. Data was considered insufficient to judge the utility of cannabis products in reducing seizure frequency or severity.[48]
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