Long-term effects of cannabis
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The long-term effects of cannabis have been the subject of ongoing debate. Because cannabis is illegal in most countries, research presents a challenge; as such, there remains much to be concluded.
- 1 Memory and intelligence
- 2 Dependency
- 3 Mental health
- 4 Gateway drug hypothesis
- 5 Physical health
- 6 See also
- 7 References
Memory and intelligence
Long-term exposure to cannabis has never been demonstrated through statistically significant data to pose any risk of irreversible cognitive impairment in children and pre-pubescent adolescents or adults as data for these types of studies does not exist and rat models using synthetic cannabinoids are not translatable to human exposures nor demonstrable in current legal climates.  Acute cannabis intoxication causes alterations in attention, psychomotor task ability, and short-term memory however a dose-response relationship has not been formally established through blinded randomized placebo controlled trials which represent the gold standard by which these factual relationships are determined. While structural changes have been shown, studies have not demonstrated causation between cannabinoids and functionally significant long-term central nervous system effects of the drug or negative changes to brain composition.  Misrepresentation of data as demonstrating significance particularly regarding cannabinoids is a rampant issue in the scientific community and many of the studies that demonstrate brain structural changes have deluded confounding variables and selection bias that renders much of their data useless with which to draw meaningful conclusions. Acute intoxication is often misrepresented as long term cognitive effects however data has demonstrated that chronic cannabis exposure requires longer to "wash out" of users and thus the acute intoxication affects appear to persist.  Adequate time for wearing off produces data that demonstrates no difference in users performance of cognitive tasks.
Cannabis is the most widely used illicit drug in the Western world, and in the US 10 to 20% of consumers who use cannabis daily become dependent. Cannabis use disorder is defined in the fifth revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) as a condition requiring treatment. A 2012 review of cannabis use and dependency in the US by Danovitch et al said that in the US, "42% of persons over age 12 have used cannabis at least once in their lifetime, 11.5% have used within the past year, and 1.8% have met diagnostic criteria for cannabis abuse or dependence within the past year. Among individuals who have ever used cannabis, conditional dependence (the proportion who go on to develop dependence) is 9%." Although no medication is known to be effective in combating dependency, combinations of psychotherapy such as cognitive behavioural therapy and motivational enhancement therapy have achieved some success.
Research has shown the overall addiction potential for cannabis to be less than for cocaine or heroin, but slightly higher than that for psilocybin, mescaline, or LSD. Dependence on cannabis tends to be less severe than that observed with cocaine, opiates, and alcohol.
Historically, the possible connection between psychosis and cannabis has been long-debated. Recent medical evidence strongly suggests that the long-term use of cannabis in people who started using it when young heightens the risk of mental health problems and other physical and development disorders, although the causal link remains to be definitively established. These risks appear to be most acute in adolescent users.
Although there has been an association noted between cases of acute psychosis and long-term cannabis use, the precise nature of the relationship is controversial; evidence suggests that cannabis use may worsen psychotic symptoms and increase the risk of relapse.
According to one review, long term cannabis use "increases the risk of psychosis in people with certain genetic or environmental vulnerabilities", but does not cause psychosis. Important predisposing factors include genetic liability, childhood trauma and urban upbringing. A second review concluded that cannabis use may cause permanent psychological disorders in some users such as cognitive impairment, anxiety, paranoia, and increased risks of psychosis. Key predisposing variables include age of first exposure, frequency of use, the potency of the cannabis used, and individual susceptibility.
Among people with schizophrenia there is insufficient evidence to determine whether cannabis use leads to improvement or deterioration of the condition, but patients who use cannabis have been found to display increased cognitive performance compared to non-users.
Use of cannabis in adolescence or earlier increases the risk of developing schizoaffective disorders in adult life, although the proportion of these cases is small. Susceptibility is most often found in users with at least one copy of the polymorphic COMT gene.
Cannabis with a high THC to CBD ratio produces a higher incidence of psychological effects. CBD may show antipsychotic and neuroprotective properties, acting as an antagonist to some of the effects of THC. Studies examining this effect have used high ratios of CBD to THC, and it is unclear to what extent these laboratory studies translate to the types of cannabis used by real life users. Research has shown that CBD can safely prevent psychosis in general.
Less attention has been given to the association between cannabis use and depression, though according to the Australian National Drug & Alcohol Research Centre, it is possible this is because cannabis users who have depression are less likely to access treatment than those with psychosis.
Teenage cannabis users show no difference from the general population in incidence of major depressive disorder (MDD), but an association exists between early exposure coupled with continued use into adult life and increased incidence of MDD in adulthood. Among cannabis users of all ages, there may be an increased risk of developing depression, with heavy users seemingly having a higher risk.
Adolescent cannabis users show no difference from their peers in suicidal ideation or rate of suicide attempts, but those who continue to use cannabis into adult life exhibit an increased incidence of both, although multiple other contributory factors are also implicated.
In the general population a weak (indirect) association appears to exist between suicidal behaviour and cannabis consumption in both psychotic and non-psychotic users, although it remains unclear whether regular cannabis use increases the risk of suicide. Cannabis use is a risk factor in suicidality, but suicide attempts are characterized by many additional risk factors including mood disorders, stress, personal problems and poor support.
Gateway drug hypothesis
A 2013 literature review said that exposure to marijuana was "associated with diseases of the liver (particularly with co-existing hepatitis C), lungs, heart, and vasculature". The authors cautioned that "evidence is needed, and further research should be considered, to prove causal associations of marijuana with many physical health conditions".
Imaging studies suggest that long-term exposure does not lead to decreases in white matter or grey matter volume, but may lead to reductions in hippocampal volume. Variations in the methodologies used lend some uncertainty to this conclusion.
A 2012 review examining the relation of cancer and cannabis found little direct evidence that cannabinoids found in cannabis, including THC, are carcinogenic. Cannabinoids are not mutagenic according to the Ames test. Cannabis smoke has been found to be carcinogenic in rodents and mutagenic in the Ames test. Correlating cannabis use with the development of human cancers has been problematic due to difficulties in quantifying cannabis use, unmeasured confounders, and cannabinoids may have anti-cancer effects.
According to a 2013 literature review, marijuana could be carcinogenic, but there are methodological limitations in studies making it difficult to establish a link between marijuana use and cancer risk. The authors say that bladder cancer does seem to be linked to habitual marijuana use, and that there may be a risk for cancers of the head and neck among long-term (more than 20 years) users. Gordon and colleagues said, "there does appear to be an increased risk of cancer (particularly head and neck, lung, and bladder cancer) for those who use marijuana over a period of time, although what length of time that this risk increases is uncertain."
In 2012 WebMD said that a number of studies had suggested a link between cannabis use and an increased risk of testicular cancer, but that the overall risk remained small and that more research is needed to confirm the findings. According to Gordon and colleagues, "several recent studies suggest an association between marijuana use and testicular germ cell tumors".
There has been a limited number of studies that have looked at the effects of smoking cannabis on the respiratory system. Chronic heavy marijuana smoking is associated with coughing, production of sputum, wheezing, and other symptoms of chronic bronchitis. Regular cannabis use has not been shown to cause significant abnormalities in lung function.
Regular cannabis smokers show pathological changes in lung cells similar to those that precede the development of lung cancer in tobacco smokers. Gordon and colleagues in a 2013 literature review said: "Unfortunately, methodological limitations in many of the reviewed studies, including selection bias, small sample size, limited generalizability, and lack of adjustment for tobacco smoking, may limit the ability to attribute cancer risk solely to marijuana use." Reviewing studies adjusted for age and tobacco use, they said there was a risk of lung cancer even after adjusting for tobacco use, but that the period of time over which the risk increases is uncertain.
A 2013 review which specifically examined the effects of cannabis on the lung concluded "Findings from a limited number of well-designed epidemiological studies do not suggest an increased risk for the development of either lung or upper airway cancer from light or moderate use, although evidence is mixed concerning possible carcinogenic risks of heavy, long-term use."
In 2013 the International Lung Cancer Consortium found no significant additional lung cancer risk in tobacco users who also smoked cannabis. Nor did they find an increased risk in cannabis smokers who did not use tobacco. They concluded that "Our pooled results showed no significant association between the intensity, duration, or cumulative consumption of cannabis smoke and the risk of lung cancer overall or in never smokers." They cautioned that "Our results cannot preclude the possibility that cannabis may exhibit an association with lung cancer risk at extremely high dosage."
Cannabis smoke contains thousands of organic and inorganic chemicals, including many of the same carcinogens as tobacco smoke. A 2012 special report by the British Lung Foundation concluded that cannabis smoking was linked to many adverse effects, including bronchitis and lung cancer. They identified cannabis smoke as a carcinogen and also said awareness of the danger was low compared with the high awareness of the dangers of smoking tobacco particularly among younger users. They said there was an increased risk from each cannabis cigarette due to drawing in large puffs of smoke and holding them. Marijuana smoke has been listed on the California Proposition 65 warning list as a carcinogen since 2009, but leaves and pure THC are not.
Head and neck
A 2011 review of studies in the US found that although some supported the hypothesis that cannabis use increased the risk of getting head and neck cancer, when other factors are accounted for the majority did not. Gordon and colleagues (2013) said there was a risk of these cancers associated with marijuana use over a long period of time. A 2015 review found no association with lifetime cannabis use and the development of head and neck cancer. 
A 2013 literature review by Gordon and colleagues concluded that inhaled marijuana is associated with lung disease, although Tashkin's 2013 review has found "no clear link to chronic obstructive pulmonary disease".
Of the various methods of cannabis consumption, smoking is considered the most harmful; the inhalation of smoke from organic materials can cause various health problems (e.g., coughing and sputum). Isoprenes help to modulate and slow down reaction rates, contributing to the significantly differing qualities of partial combustion products from various sources.
Smoking cannabis has been linked to adverse respiratory effects including: chronic coughing, wheezing, sputum production, and acute bronchitis. It has been suggested that the common practice of inhaling cannabis smoke deeply and holding breath could lead to pneumothorax. In a few case reports involving immunocompromised patients, pulmonary infections such as aspergillosis have been attributed to smoking cannabis contaminated with fungi. The transmission of tuberculosis has been linked to cannabis inhalation techniques, such as sharing water pipes and 'Hotboxing'.
Reproductive and endocrine effects
Cannabis consumption in pregnancy is associated with restrictions in growth of the fetus, miscarriage, and cognitive deficits in offspring. Although the majority of research has concentrated on the adverse effects of alcohol, there is now evidence that prenatal exposure to cannabis has serious effects on the developing brain and is associated with "deficits in language, attention, areas of cognitive performance, and delinquent behavior in adolescence". A report prepared for the Australian National Council on Drugs concluded cannabis and other cannabinoids are contraindicated in pregnancy as it may interact with the endocannabinoid system.
No fatal overdoses associated with cannabis use have been reported. Due to the small number of studies that have been conducted, the evidence is insufficient to show an elevated risk of mortality from all causes (including suicide) among cannabis users, although some studies imply that motor vehicle fatalities, and possibly respiratory and brain cancers, may have a higher risk among heavy users.
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