The Adverse Effects of Marijuana (for healthcare professionals)

Introduction

Before reviewing the health effects of marijuana, a few points of clarification are indicated:

First, to talk about the health effects of "marijuana" is actually to talk about a wide range of compounds typically found in the cannabis plant. While the prominent role of THC in producing marijuana intoxication makes it the most frequently discussed compound, in fact it is only one of a wide range of compounds found in marijuana that have an important impact on health. A number of factors determine what is ingested when a person uses marijuana. These include variations in plant strain, cultivation technique, mode of harvest, and route of ingestion.

Second, a differentiation will be made between the acute and chronic effects of marijuana. Most users are familiar with the acute intoxication caused by marijuana. However, subtle effects may go un-noticed in the short term, only becoming detectable cumulatively with chronic use.

Third, this discussion will separately address the impact of marijuana on physical health, mental health, perinatal health, and brain function. Scientific studies have tended to investigate these areas independently. Within the human body, however, these areas are inextricably bound, each having important bi-directional effects on the other.

Brain Function

Short Term Effects on Cognition
Marijuana intoxication is the result of a number of brain changes that occur when marijuana is used. These include alterations in short-term memory, sense of time, sensory perception, attention span, problem solving, verbal fluency, reaction time, and psychomotor control (Iversen 2003). Some users report positive feelings such as mild euphoria and relaxation, while others, particularly naive users, report anxiety, paranoia, and panic reactions (Hall and Degenhardt 2009). The short term effects of marijuana last approximately 1-4 hours, depending on potency of the marijuana, the route of administration, and the tolerance of the user. While frequent users develop tolerance to many of marijuana's effects, tolerance is never complete; even users who do not appear or feel intoxicated continue to manifest impairments under testing (Bolla, Brown et al. 2002; Wadsworth, Moss et al. 2006).

A special note of caution is warranted with regards to marijuana and driving. In one recent study, 97% of heavy users of marijuana reported driving a car while intoxicated(Terry and Wright 2005). Many users justified their ability to drive by comparing the effects of marijuana to the effects of alcohol. Marijuana does cause less dramatic impairment than alcohol intoxication, but it has nonetheless been associated with a 2-3 fold increase in accidents on the road (Drummer, Gerostamoulos et al. 2004; Ramaekers, Berghaus et al. 2004). An association has been found between blood THC levels and likelihood of culpability in fatal traffic accidents involving marijuana users (Grotenhermen, Leson et al. 2007). The increase in accidents is likely related to the effects of marijuana on attention, hand-eye coordination, tracking behavior and reaction time (Ramaekers, Berghaus et al. 2004). Even individuals with tolerance, who may not show obvious deficits in these areas, manifest impairment when there is a need to adaptively respond to sudden unexpected emergencies (Liguori, Gatto et al. 1998). The combination of alcohol and marijuana produces levels of impairment greater than their independent sum, and this too has been demonstrated among experienced users with high levels of tolerance (Bramness, Khiabani et al.; Liguori, Gatto et al. 2002).

Long Term Effects on Cognition
While there is no question that marijuana causes short-term impairments in brain function, the degree to which these impairments are reversible with chronic use is less clear. Some studies have shown that brain function recovers over time, while others demonstrate persistence of subtle, but important, impairments. How is it possible to reconcile the different findings from different studies? These inconsistencies often appear to reflect differences in the sensitivity with which "impairment" is measured. By and large, most of the prominent brain effects of marijuana are short term and do in fact reverse when marijuana is discontinued. However, there is increasing evidence that subtle effects, such as slowed information processing, may actually persist long after discontinuation. These effects are difficult to detect because they may only become apparent in the setting of highly complex, demanding brain functions (Solowij, Stephens et al. 2002).

The psychoactive effects of marijuana are thought to be predominantly mediated by THC stimulation of brain cannabinoid (CB1) receptors. Acute and chronic marijuana use cause changes in brain function, as demonstrated by measures of cerebral blood flow, glucose metabolism, electrophysiology, and structural anatomy (Schweinsburg, Brown et al. 2008). Functional imaging studies have shown less activity in brain regions involved in memory and attention in chronic marijuana users than in non-users, even after 28 days of abstinence (Block, O'Leary et al. 2002; Quickfall and Crockford 2006). Long-term marijuana users have also been shown to have reduced volumes of the hippocampus and amygdala, consistent with animal studies that demonstrate up to a 44% persistent decrease in hippocampal synapses in rats dosed with THC for 90 days (Scallet, Uemura et al. 1987; Yucel, Solowij et al. 2008). Downregulation of CB1 receptors between 20-60% in different areas of the brain account for the development of tolerance to some of marijuana's effects (Romero, Garcia-Palomero et al. 1997). Increasing endogenous cannabinoid activity by administering URB597 to block anandamide metabolism in adolescent rats produces long-lasting decreases in CB1 binding in caudate-putamen, nucleus accumbens, ventral tegmental area and hippocampus (Marco, Rubino et al. 2009).

Cannabinoid receptors are most prevalent in the prefrontal cortex, hippocampus, amygdala, basal ganglia, and cerebellum. These brain regions undergo prominent developmental changes throughout childhood and adolescence, and thus may be particularly susceptible to the adverse cognitive effects of marijuana. Adolescent humans using marijuana have been found to have increased volumes in the cerebellum, possibly from failure to prune synapses effectively (Medina, Nagel et al.). These adolescent marijuana users also show increased brain processing effort on fMRI during an inhibition task in the presence of similar task performance, even after 28 days of abstinence (Tapert, Schweinsburg et al. 2007). Taken together, there is compelling evidence that chronic increases in stimulation of the brain's cannabinoid system can lead to morphologic and physiologic changes especially during adolescence (Schweinsburg, Brown et al. 2008).

Physical Health

Lungs
Smoked marijuana irritates the delicate lining of the respiratory tract and causes damage to the cells lining the bronchial passages. This damage impairs the respiratory system's ability to clear toxins and fight off microorganisms. It also leads to inflammatory changes, which are experienced by users in the symptoms of increased phlegm, cough, wheezing, and shortness of breath(Kalant 2004).Users of marijuana are at increased risk of both acute and chronic bronchitis. When combined with tobacco smoke, there are additive effects causing COPD (Taylor, Fergusson et al. 2002).

Cancer
Smoked marijuana is also thought to carry a risk of cancer, particularly lung cancer and cancer of the head and neck (Zhang, Morgenstern et al. 1999; Tashkin, Baldwin et al. 2002). This concern emerges from the observation that heavy marijuana use causes biochemical and gene alterations in the respiratory tract that are known to be markers of precancerous change(Kalant 2004). Further, marijuana smoke has many of the same carcinogenic hydrocarbons that have been shown to cause lung cancer from tobacco (Denissenko, Pao et al. 1996). Unfortunately, marijuana has not been studied as thoroughly as other smokeable products such as tobacco, and most of the existing studies indicate "risk," not "proof," of a relationship to developing cancer.

In 2006, an analysis of multiple studies investigating marijuana and cancer, revealed the following observations (Mehra, Moore et al. 2006):

  1. Smoking marijuana results in the delivery of tar to the lungs. Tar is a residue in smoke carrying many carcinogens. Tar exposure increases with large inhalations and breath-holding. Pound for pound, the quantity of tar inhaled through smoking marijuana is greater than from smoking tobacco.
  2. Smoking marijuana has been shown to cause "metaplastic changes" in the respiratory cells of some users. "Metaplastic change" describes the developmental phases cells go through as they develop from normal cells to cancer cells.
  3. Smoking marijuana impairs the function of cells called alveolar macrophages. These cells are the part of the body's immune system responsible for removing tumor cells from the lungs.

Heart
Marijuana increases heart rate and mildly increases in blood pressure, which combine to force the heart to work more strenuously. This increased workload has not been associated with pathology among healthy individuals, whose hearts have substantial reserve. However among those with pre-existing heart disease, marijuana can have serious adverse effects. One large study of 3882 patients who had heart attacks showed that in the hour after smoking marijuana users were 4.8 fold more likely than non-users to have heart attacks (Mittleman, Lewis et al. 2001). 1913 of these patients were followed prospectively, and a dose-response relationship was reported between their marijuana use and mortality over the following 4 years. Compared with non-users, those who smoked marijuana weekly had a 2.5 fold greater likelihood of heart attack, and those who smoked more than one time per week had a 4.2 fold increased risk.

Reproductive and Perinatal Effects
Basic science research outstrips clinical research in the complex area of the role endocannabinoids play in all aspects of human reproduction and the impact of exogenous cannabinoids (i.e., the THC and other cannabinoid compounds in marijuana) on reproductive physiology. Animal studies have demonstrated the existence of CB1 receptors, endogenous cannabinoid ligands and the degradation by fatty acid amide hydrolase (FAAH) in sperm, eggs, and preimplantation embryos (Schuel 2006). Studies have found a critical balance between anandamide synthesis and its degradation by FAAH in mouse embryos and oviducts necessary for normal embryo development, oviductal transport, implantation and pregnancy (Wang, Guo et al. 2004; Wang, Xie et al. 2006). As a result, marijuana and THC have been shown in animal models to effect multiple aspects of reproductive physiology, including secretion of gonadotrphic hormones by the pituitary and sex steroids by the gonands, sperm production and capacitation, ovulation, fertilization, early embryonic devepoment, implantation, placental functions, fetal growth, number of pregnancies carried to term, lactation, suckling behavior by newborns and growth of malignant breast and prostate cells (Schuel 2006). The clinical implications of these basic science findings for human reproduction remains unclear despite the fact that animal studies show that exogenous THC can swamp endogenous anadamide signaling systems, thereby affecting multiple physiological processes.

The question of marijuana and birth defects perfectly illustrates the disparity between basic science and clinical research. The California Teratogen Information Service (CTIS) fact sheet on marijuana and pregnancy reports that the frequency of birth defects was not increased in the babies of 1246 women who reported occasionally smoking marijuana during pregnancy (CTIS). However, mutations in lymphocyte are increased in cord blood of infants exposed to THC in utero and surveys have found an increase in specific birth defects, including ventricular septal defect, in offspring of marijuana smokers (Ammenheuser, Berenson et al. 1998; Forrester and Merz 2007). As with use of all drugs during pregnancy, caution is advised even in the face of inconclusive evidence.

Many of the compounds in smoked marijuana readily cross the placenta, where the growing fetus absorbs them, and pass into breast milk, where nursing infants ingest them. Because it is not ethical to give pregnant or nursing women marijuana, most of the studies in this area have followed groups of women who have been identified as smoking marijuana during those risk periods. Interpretation of these studies is limited by confounding valiables such as the fact that pregnant marijuana users are also more likely to use other illicit drugs, tobacco, alcohol, and less likely to receive antenatal care. Nonetheless, studies show that marijuana use during pregnancy or breast feeding is linked with the following outcomes: Low birth weight; developmental delay; and behavioral problems (Fergusson, Horwood et al. 2002). Are these short term or long term effects? Monitoring these effects over time suggests that some of these effects may persist throughout a child's development, and that early exposure to marijuana is associated with behavioral problems at age 10 (Goldschmidt, Richardson et al. 2004), and an increased risk of marijuana use at age 14(Day, Goldschmidt et al. 2006). Altogether, the effects of marijuana on child development appear to be subtle but significant, particularly given what is known about the importance of the early years as a critical period for establishing a foundation for growth and function throughout the rest of life.

Psycho-Social Health

Dependence
Information on the addictive potential of marijuana is provided in greater detail on two separate web pages. In summary, marijuana has been shown to be addicting to 9% of people who begin smoking at 18 years or older. Withdrawal symptoms -- irritability, anxiety, sleep disturbances -- often contribute to relapse. Because adolescent brains are still developing, marijuana use before 18 results in higher rates of addiction -- up to 17% within 2 years -- and disruption to an individual's life. The younger the use, the greater the risk.

Mental Health
Marijuana is well known to cause fluctuations in mood and anxiety, but the extent to which these fluctuations persist beyond the period of marijuana use is unclear (de Graaf, Radovanovic et al.). Studies show an increase in anxiety and depressive disorders among frequent marijuana users, but there is not sufficient information to determine the direction of causality (Bovasso 2001). In other words, we cannot yet determine whether marijuana causes an increase in depression and anxiety, or whether individuals who suffer from depression and anxiety tend to use more marijuana (Degenhardt, Hall et al. 2003). However, heavier marijuana use has been shown to increase the association with anxiety and depression and weekly or more frequent cannabis use in teenagers predicts an approximately twofold increase in risk for later depression and anxiety (Degenhardt, Hall et al. 2001; Patton, Coffey et al. 2002)

The hypothalimis-pituitary-adrenal axis is known to be modulated by the endogenous cannabinoid system (Cota 2008). Exogenous cannabinoids such as THC have long been known to activate the major neuroendocrine stress response system of mammals via the HPA axis (Steiner and Wotjak 2008). Dysregulation of stress responses are often related to mood instability. Consistent with this, functional MRI imaging demonstrates altered activation of frontal and limbic systems chronic heavy marijuana smokers, suggesting differences in affective processing (Gruber, Rogowska et al. 2009).

In sufficient doses, marijuana can cause psychosis (Moore, Zammit et al. 2007), a state of mind characterized by the inability to distinguish between what is real and what is not. Psychosis is concerning for three reasons: First, the loss of connection to reality can be an emotionally terrifying experience. Second, psychosis can stimulate unsafe behavior when the lack of connection to reality inhibits the ability to determine what is safe and what is not. Third, there is mounting evidence that psychosis itself is harmful to the brain, and may actually predispose the brain to psychotic disorders (Perkins, Gu et al. 2005).

In addition to causing psychosis, marijuana may also contribute to the development of life long psychotic disorders such as schizophrenia (Degenhardt, Hall et al. 2003). Schizophrenia is a disorder characterized by deterioration in thinking, disturbances in perception, and impairments in social function. Marijuana can unmask symptoms among individuals who have pre-existing vulnerability (such as a family history) to schizophrenia (Arseneault, Cannon et al. 2004). Additionally, marijuana may be an independent risk factor for the development of psychotic disorders such as schizophrenia. Schizophrenia affects approximately 1% of the population across the world, and marijuana has been found to increase the risk of manifesting the illness by 1.4 to 2 fold (Moore, Zammit et al. 2007). Marijuana use by schizophrenics has been associated with brain volume loss significantly greater than seen in schizophrenics who abstain from marijuana (Rais, Cahn et al. 2008).

Social Function
A relationship between marijuana and poor educational attainment has been repeatedly demonstrated across many studies (Hall, Degenhardt et al. 2001). The relationship appears to hold even when confounding variables are statistically controlled Fergusson, Horwood et al. 2003). School performance is a function of many factors, but it is likely that the short-term effects of marijuana intoxication exacerbate existing school difficulties, and push poor performance into school failure. On the other hand, analysis of behavioral, socioeconomic, and health outcomes at age 29 all reveal that abstainers consistently have the most favorable outcomes, whereas early high users consistently have the least favorable outcomes (Ellickson, Martino et al. 2004). A 21-year longitudinal study of 1265 New Zealand adolescents found that regular or heavy use, was associated with increased rates of a range of adjustment problems, including other illicit drug use, crime, depression and suicidal behaviours (Fergusson, Horwood et al. 2002).

The association between marijuana and other adverse social outcomes (such as unemployment, status of occupation, income, unplanned pregnancy, alcohol and illicit substance use, crime, and incarceration) may, however, be mediated by the downstream impact of school failure and low educational attainment (Hall, Degenhardt et al. 2001). Criminalization of marijuana may also contribute to these adverse outcomes via the adverse lifelong consequences of a criminal record or incarceration (MacCoun 1993).

Conclusion

We borrow a concluding summary from "Adverse health effects of non-medical cannabis use" by Hall and Degenhardt (www.the lancet.com Vol 374, October 17, 2009), two senior Australian researchers, to avoid unintended blindspots commonly found in summaries penned by American authors (Hall and Degenhardt 2009):

"Acute adverse effects of cannabis use include anxiety and panic in naive users, and a probable increased risk of accidents if users drive while intoxicated (panel 1). Use during pregnancy could reduce birthweight, but does not seem to cause birth defects. Whether cannabis contributes to behavioural disorders in the off spring of women who smoked cannabis during pregnancy is uncertain.

"Chronic cannabis use can produce a dependence syndrome in as many as one in ten users. Regular users have a higher risk of chronic bronchitis and impaired respiratory function, and psychotic symptoms and disorders, most probably if they have a history of psychotic symptoms or a family history of these disorders. The most probable adverse psychosocial effect in adolescents who become regular users is impaired educational attainment. Adolescent regular cannabis users are more likely to use other illicit drugs, although the explanation of this association remains contested. Regular cannabis use in adolescence might also adversely affect mental health in young adults, with the strongest evidence for an increased risk of psychotic symptoms and disorders.

"Some other adverse effects are associated with regular cannabis use (panel 2), but whether they are causal is not known because of the possible confounding effects of other drugs (tobacco for respiratory cancers; tobacco, alcohol, and other drugs for behavioural disorders in children whose mothers smoked cannabis during pregnancy). In the case of depressive disorders and suicide, the association with cannabis is uncertain. For cognitive performance, the size and reversibility of the impairment remain unclear. The focus of epidemiological and clinical research should be on clarifying the causative role of cannabis for these adverse health effects.

"The public health burden of cannabis use is probably modest compared with that of alcohol, tobacco, and other illicit drugs. A recent Australian study (Begg, Vos et al. 2008) estimated that cannabis use caused 0.2% of total disease burden in Australia-a country with one of the highest reported rates of cannabis use. Cannabis accounted for 10% of the burden attributable to all illicit drugs (including heroin, cocaine, and amphetamines). It also accounted for around 10% of the proportion of disease burden attributed to alcohol (2.3%), but only 2.5% of that attributable to tobacco (7.8%)."

Panel 1: Acute and chronic adverse effects of cannabis use

Acute adverse effects

  • Anxiety and panic, especially in naive users
  • Psychotic symptoms (at high doses)
  • Road crashes if a person drives while intoxicated

Chronic adverse effects

  • Cannabis dependence syndrome (in around one in ten users)
  • Chronic bronchitis and impaired respiratory function in regular smokers
  • Psychotic symptoms and disorders in heavy users, especially those with a history of psychotic symptoms or a family history of these disorders
  • Impaired educational attainment in adolescents who are regular users
  • Subtle cognitive impairment in those who are daily users for 10 years or more

Panel 2: Possible adverse effects of regular cannabis use with unknown causal relation

  • Respiratory cancers
  • Behavioural disorders in children whose mothers used cannabis while pregnant
  • Depressive disorders, mania, and suicide
  • Use of other illicit drugs by adolescents

 

Ammenheuser, M. M., et al. (1980). "Frequencies of hprt mutant lymphocytes in marijuana-smoking mothers and their newborns." Mutat Res 403(1-2): 55-64.
Reports of increases in the prevalence of marijuana smoking, especially among young people, have led to concerns about possible genotoxic effects from marijuana use due to exposure to the mutagenic and carcinogenic agents present in marijuana smoke. Prior studies of the adverse health consequences of marijuana smoking, using disease outcomes, have sometimes been confounded by the fact that most marijuana smokers also smoke tobacco. In the present study, the potential mutagenic effects of marijuana smoking were investigated with a somatic cell mutation assay that detects mutations occurring in vivo in the hprt gene. Subjects were volunteers recruited from a prenatal clinic that performs urine drug screens on all consenting patients. Blood samples were collected from 17 subjects whose drug screens indicated marijuana use, but who did not smoke tobacco or use cocaine or opiates, and 17 non-smokers with negative drug screens. Absence of tobacco use was confirmed by plasma cotinine tests. Cord blood samples were collected from newborns of 5 of the marijuana smokers and 5 non-smokers. Lymphocytes were isolated, cryopreserved, and later thawed and assayed with the autoradiographic hprt assay. The frequency of variant (mutant) lymphocytes (Vf) in the 17 non-smokers (+/- standard error) was 1.93 (+/- 0.17) per million evaluatable cells. The Vf of 17 marijuana smokers was more than three-fold higher, 6.48 (+/- 0.48) x 10(-6), a significant difference, p < 0.001. Cord blood lymphocytes from 5 newborns of non-smokers had a Vf of 0.85 (+/- 0.23) x 10(-6), compared to 2.55 (+/- 0.60) x 10(-6) for 5 newborns of marijuana smokers, significantly higher, p < 0.05. Because of the known association between increases in somatic mutations and the development of malignancies, this study indicates that marijuana smokers may have an elevated risk of cancer. For pregnant marijuana smokers, there is also concern for the possibility of genotoxic effects on the fetus, resulting in heightened risk of birth defects or childhood cancer.

Ammenheuser, M. M., A. B. Berenson, et al. (1998). "Frequencies of hprt mutant lymphocytes in marijuana-smoking mothers and their newborns." Mutat Res 403(1-2): 55-64.
Reports of increases in the prevalence of marijuana smoking, especially among young people, have led to concerns about possible genotoxic effects from marijuana use due to exposure to the mutagenic and carcinogenic agents present in marijuana smoke. Prior studies of the adverse health consequences of marijuana smoking, using disease outcomes, have sometimes been confounded by the fact that most marijuana smokers also smoke tobacco. In the present study, the potential mutagenic effects of marijuana smoking were investigated with a somatic cell mutation assay that detects mutations occurring in vivo in the hprt gene. Subjects were volunteers recruited from a prenatal clinic that performs urine drug screens on all consenting patients. Blood samples were collected from 17 subjects whose drug screens indicated marijuana use, but who did not smoke tobacco or use cocaine or opiates, and 17 non-smokers with negative drug screens. Absence of tobacco use was confirmed by plasma cotinine tests. Cord blood samples were collected from newborns of 5 of the marijuana smokers and 5 non-smokers. Lymphocytes were isolated, cryopreserved, and later thawed and assayed with the autoradiographic hprt assay. The frequency of variant (mutant) lymphocytes (Vf) in the 17 non-smokers (+/- standard error) was 1.93 (+/- 0.17) per million evaluatable cells. The Vf of 17 marijuana smokers was more than three-fold higher, 6.48 (+/- 0.48) x 10(-6), a significant difference, p < 0.001. Cord blood lymphocytes from 5 newborns of non-smokers had a Vf of 0.85 (+/- 0.23) x 10(-6), compared to 2.55 (+/- 0.60) x 10(-6) for 5 newborns of marijuana smokers, significantly higher, p < 0.05. Because of the known association between increases in somatic mutations and the development of malignancies, this study indicates that marijuana smokers may have an elevated risk of cancer. For pregnant marijuana smokers, there is also concern for the possibility of genotoxic effects on the fetus, resulting in heightened risk of birth defects or childhood cancer.

Arseneault, L., M. Cannon, et al. (2004). "Causal association between cannabis and psychosis: examination of the evidence." Br J Psychiatry 184: 110-7.
BACKGROUND: Controversy remains as to whether cannabis acts as a causal risk factor for schizophrenia or other functional psychotic illnesses. AIMS: To examine critically the evidence that cannabis causes psychosis using established criteria of causality. METHOD: We identified five studies that included a well-defined sample drawn from population-based registers or cohorts and used prospective measures of cannabis use and adult psychosis. RESULTS: On an individual level, cannabis use confers an overall twofold increase in the relative risk for later schizophrenia. At the population level, elimination of cannabis use would reduce the incidence of schizophrenia by approximately 8%, assuming a causal relationship. Cannabis use appears to be neither a sufficient nor a necessary cause for psychosis. It is a component cause, part of a complex constellation of factors leading to psychosis. CONCLUSIONS: Cases of psychotic disorder could be prevented by discouraging cannabis use among vulnerable youths. Research is needed to understand the mechanisms by which cannabis causes psychosis.

Begg, S. J., T. Vos, et al. (2008). "Burden of disease and injury in Australia in the new millennium: measuring health loss from diseases, injuries and risk factors." Med J Aust 188(1): 36-40.
OBJECTIVE: To describe the magnitude and distribution of health problems in Australia, in order to identify key opportunities for health gain. DESIGN: Descriptive epidemiological models for a comprehensive set of diseases and injuries of public health importance in Australia were developed using a range of data sources, methods and assumptions. Health loss associated with each condition was derived using normative techniques and quantified for various subpopulations, risks to health, and points in time. The baseline year for comparisons was 2003. MAIN OUTCOME MEASURES: Health loss expressed as disability-adjusted life years (DALYs) and presented as proportions of total DALYs and DALY rates (crude and age-standardised) per 1000 population. RESULTS: A third of total health loss in 2003 was explained by 14 selected health risks. DALY rates were 31.7% higher in the lowest socioeconomic quintile than in the highest, and 26.5% higher in remote areas than in major cities. Total DALY rates were estimated to decline for most conditions over the 20 years from 2003 to 2023, but for some causes, most notably diabetes, they were projected to increase. CONCLUSION: Despite steady improvements in Australia's health over the past decade, there are still opportunities for further progress. Significant gains can be made through achievable changes in exposure to a limited number of well established health risks.

Block, R. I., D. S. O'Leary, et al. (2002). "Effects of frequent marijuana use on memory-related regional cerebral blood flow." Pharmacol Biochem Behav 72(1-2): 237-50.
It is uncertain whether frequent marijuana use adversely affects human brain function. Using positron emission tomography (PET), memory-related regional cerebral blood flow was compared in frequent marijuana users and nonusing control subjects after 26+ h of monitored abstention. Memory-related blood flow in marijuana users, relative to control subjects, showed decreases in prefrontal cortex, increases in memory-relevant regions of cerebellum, and altered lateralization in hippocampus. Marijuana users differed most in brain activity related to episodic memory encoding. In learning a word list to criterion over multiple trials, marijuana users, relative to control subjects, required means of 2.7 more presentations during initial learning and 3.1 more presentations during subsequent relearning. In single-trial recall, marijuana users appeared to rely more on short-term memory, recalling 23% more than control subjects from the end of a list, but 19% less from the middle. These findings indicate altered memory-related brain function in marijuana users.

Bolla, K. I., K. Brown, et al. (2002). "Dose-related neurocognitive effects of marijuana use." Neurology 59(9): 1337-43.
BACKGROUND: Although about 7 million people in the US population use marijuana at least weekly, there is a paucity of scientific data on persistent neurocognitive effects of marijuana use. OBJECTIVE: To determine if neurocognitive deficits persist in 28-day abstinent heavy marijuana users and if these deficits are dose-related to the number of marijuana joints smoked per week. METHODS: A battery of neurocognitive tests was given to 28-day abstinent heavy marijuana abusers. RESULTS: As joints smoked per week increased, performance decreased on tests measuring memory, executive functioning, psychomotor speed, and manual dexterity. When dividing the group into light, middle, and heavy user groups, the heavy group performed significantly below the light group on 5 of 35 measures and the size of the effect ranged from 3.00 to 4.20 SD units. Duration of use had little effect on neurocognitive performance. CONCLUSIONS: Very heavy use of marijuana is associated with persistent decrements in neurocognitive performance even after 28 days of abstinence. It is unclear if these decrements will resolve with continued abstinence or become progressively worse with continued heavy marijuana use.

Bovasso, G. B. (2001). "Cannabis abuse as a risk factor for depressive symptoms." Am J Psychiatry 158(12): 2033-7.
OBJECTIVE: This study sought to estimate the degree to which cannabis abuse is a risk factor for depressive symptoms rather than an effort to self-medicate depression. METHOD: Participants (N=1,920) in the 1980 Baltimore Epidemiologic Catchment Area (ECA) study who were reassessed between 1994 and 1996 as part of a follow-up study provided the data. The analysis focused on two cohorts: those who reported no depressive symptoms at baseline (N=849) and those with no diagnosis of cannabis abuse at baseline (N=1,837). Symptoms of depression, cannabis abuse, and other psychiatric disorders were assessed with the Diagnostic Interview Schedule. RESULTS: In participants with no baseline depressive symptoms, those with a diagnosis of cannabis abuse at baseline were four times more likely than those with no cannabis abuse diagnosis to have depressive symptoms at the follow-up assessment, after adjusting for age, gender, antisocial symptoms, and other baseline covariates. In particular, these participants were more likely to have experienced suicidal ideation and anhedonia during the follow-up period. Among the participants who had no diagnosis of cannabis abuse at baseline, depressive symptoms at baseline failed to significantly predict cannabis abuse at the follow-up assessment. CONCLUSIONS: Further research is needed to identify characteristics of individuals who abuse cannabis that account for their higher risk of depression to estimate the degree of impairment resulting from their depression.

Bramness, J. G., H. Z. Khiabani, et al. "Impairment due to cannabis and ethanol: clinical signs and additive effects." Addiction 105(6): 1080-7.
AIMS: Studies have shown that the impairing effects of Delta-9-tetrahydrocannabinol (THC) are dose-related. Cannabis intake increases the risk of traffic accidents. The purpose of this study was to see how different clinical tests and observations were related to blood THC concentrations and to determine whether the combined influence of THC and ethanol was different from either drug alone. DESIGN: A retrospective cross-sectional forensic database study. SETTING: Drivers apprehended by the police suspected of driving under the influence of alcohol and other drugs. PARTICIPANTS: We investigated 589 cases positive for THC only. In addition, 894 cases with THC and ethanol were included. A comparison was made with 3480 drivers with only ethanol in their blood and 79 drivers who tested negative. MEASUREMENTS: Data were analytical results of blood samples and the 27 clinical tests and observations included in the Norwegian clinical test for impairment (CTI). FINDINGS: No relationship was found between blood THC concentration and most of the CTI tests. Blood THC concentration was, however, related to conjunctival injection, pupil dilation and reaction to light and to the overall risk of being judged impaired. When THC and ethanol were detected together the risk of being judged impaired was increased markedly. CONCLUSIONS: This study demonstrates that cannabis impairs driving ability in a concentration-related manner. The effect is smaller than for ethanol. The effect of ethanol and cannabis taken simultaneously is additive. Conjunctival injection, dilated pupils and slow pupil reaction are among the few signs to reveal THC influence.

Cota, D. (2008). "The role of the endocannabinoid system in the regulation of hypothalamic-pituitary-adrenal axis activity." J Neuroendocrinol 20 Suppl 1: 35-8.
The endocannabinoid system (ECS) is a recently identified neuromodulatory system, which is involved in several physiological processes and in disease. For example, the ECS not only represents the biological substrate of marijuana's effects, but also is known to modulate several neuroendocrine axes, including the hypothalamic-pituitary-adrenal (HPA) axis. Although previous pharmacological studies using plant-derived or synthetic cannabinoids have implied a stimulating action on the HPA axis, more recent findings have led to the conclusion that an endogenous cannabinoid tone might exist, which is actually inhibiting the release of both adrenocorticotrophic hormone and glucocorticoids. Studies using mice lacking cannabinoid receptor CB(1) have demonstrated that presence and activity of these receptors is essential for the regulation of HPA axis activity. Interestingly, the effects of endocannabinoids on the HPA axis are consistent with their neuromodulatory action on brain neurotransmitter systems. Endocannabinoids have been found to mediate the nongenomic glucocorticoid-induced inhibition of the release of corticotrophin-releasing factor within the paraventricular nucleus of the hypothalamus. Altogether, these observations suggest that alterations of the endocannabinoid tone might be associated with the development of stress-related diseases, including anxiety, depression and obesity.

CTIS, C. T. I. S. a. C. R. P. "Marijuana Fact Sheet." Retrieved August 9th, 2010, from http://ctispregnancy.org/FactSheets/IllegalDrugs/tabid/89/Default.aspx.

Day, N. L., L. Goldschmidt, et al. (2006). "Prenatal marijuana exposure contributes to the prediction of marijuana use at age 14." Addiction 101(9): 1313-22.
AIM: To evaluate the effects of prenatal marijuana exposure (PME) on the age of onset and frequency of marijuana use while controlling for identified confounds of early marijuana use among 14-year-olds. DESIGN: In this longitudinal cohort study, women were recruited in their fourth prenatal month. Women and children were followed throughout pregnancy and at multiple time-points into adolescence. SETTING AND PARTICIPANTS: Recruitment was from a hospital-based prenatal clinic. The women ranged in age from 18 to 42, half were African American and half Caucasian, and most were of lower socio-economic status. The women were generally light to moderate substance users during pregnancy and subsequently. At 14 years, 580 of the 763 offspring-mother pairs (76%) were assessed. A total of 563 pairs (74%) was included in this analysis. MEASUREMENTS: Socio-demographic, environmental, psychological, behavioral, biological and developmental factors were assessed. Outcomes were age of onset and frequency of marijuana use at age 14. PME predicted age of onset and frequency of marijuana use among the 14-year-old offspring. This finding was significant after controlling for other variables including the child's current alcohol and tobacco use, pubertal stage, sexual activity, delinquency, peer drug use, family history of drug abuse and characteristics of the home environment including parental depression, current drug use and strictness/supervision. CONCLUSIONS: Prenatal exposure to marijuana, in addition to other factors, is a significant predictor of marijuana use at age 14.

de Graaf, R., M. Radovanovic, et al. "Early cannabis use and estimated risk of later onset of depression spells: Epidemiologic evidence from the population-based World Health Organization World Mental Health Survey Initiative." Am J Epidemiol 172(2): 149-59.
Early-onset cannabis use is widespread in many countries and might cause later onset of depression. Sound epidemiologic data across countries are missing. The authors estimated the suspected causal association that links early-onset (age <17 years) cannabis use with later-onset (age > or =17 years) risk of a depression spell, using data on 85,088 subjects from 17 countries participating in the population-based World Health Organization World Mental Health Survey Initiative (2001-2005). In all surveys, multistage household probability samples were evaluated with a fully structured diagnostic interview for assessment of psychiatric conditions. The association between early-onset cannabis use and later risk of a depression spell was studied using conditional logistic regression with local area matching of cases and controls, controlling for sex, age, tobacco use, and other mental health problems. The overall association was modest (controlled for sex and age, risk ratio = 1.5, 95% confidence interval: 1.4, 1.7), was statistically robust in 5 countries, and showed no sex difference. The association did not change appreciably with statistical adjustment for mental health problems, except for childhood conduct problems, which reduced the association to nonsignificance. This study did not allow differentiation of levels of cannabis use; this issue deserves consideration in future research.

Degenhardt, L., W. Hall, et al. (2001). "The relationship between cannabis use, depression and anxiety among Australian adults: findings from the National Survey of Mental Health and Well-Being." Soc Psychiatry Psychiatr Epidemiol 36(5): 219-27.
BACKGROUND: This study aimed to examine the patterns of association between cannabis use, and anxiety and affective disorders, in the general population. METHOD: Data from the Australian National Survey of Mental Health and Well-Being, a representative survey of Australians aged 18 years and over, were analysed to address the following questions: (1) is there an association between cannabis use, DSM-IV abuse and dependence, and DSM-IV affective and anxiety disorders; (2) if so, is it explained by: demographic characteristics, levels of neuroticism, or other drug use; and (3) does the presence of a comorbid affective or anxiety disorder affect the likelihood of treatment seeking among cannabis users? RESULTS: There was a moderate univariate association between involvement with cannabis use in the past 12 months and the prevalence of affective and anxiety disorders. Among those with DSM-IV cannabis dependence, 14% met criteria for an affective disorder, compared to 6% of non-users; while 17% met criteria for an anxiety disorder, compared to 5% of non-users. These associations did not remain significant after including demographics, neuroticism and other drug use in multiple regressions. CONCLUSIONS: Cannabis use did not appear to be directly related to depression or anxiety when account was taken of other drug use. However, the association between heavier involvement with cannabis use and affective and anxiety disorders has implications for the treatment of persons with problematic cannabis use.

Degenhardt, L., W. Hall, et al. (2003). "Exploring the association between cannabis use and depression." Addiction 98(11): 1493-504.
AIM: To examine the evidence on the association between cannabis and depression and evaluate competing explanations of the association. METHODS: A search of Medline, Psychinfo and EMBASE databases was conducted. All references in which the terms 'cannabis', 'marijuana' or 'cannabinoid', and in which the words 'depression/depressive disorder/depressed', 'mood', 'mood disorder' or 'dysthymia' were collected. Only research studies were reviewed. Case reports are not discussed. RESULTS: There was a modest association between heavy or problematic cannabis use and depression in cohort studies and well-designed cross-sectional studies in the general population. Little evidence was found for an association between depression and infrequent cannabis use. A number of studies found a modest association between early-onset, regular cannabis use and later depression, which persisted after controlling for potential confounding variables. There was little evidence of an increased risk of later cannabis use among people with depression and hence little support for the self-medication hypothesis. There have been a limited number of studies that have controlled for potential confounding variables in the association between heavy cannabis use and depression. These have found that the risk is much reduced by statistical control but a modest relationship remains. CONCLUSIONS: Heavy cannabis use and depression are associated and evidence from longitudinal studies suggests that heavy cannabis use may increase depressive symptoms among some users. It is still too early, however, to rule out the hypothesis that the association is due to common social, family and contextual factors that increase risks of both heavy cannabis use and depression. Longitudinal studies and studies of twins discordant for heavy cannabis use and depression are needed to rule out common causes. If the relationship is causal, then on current patterns of cannabis use in the most developed societies cannabis use makes, at most, a modest contribution to the population prevalence of depression.

Degenhardt, L., W. Hall, et al. (2003). "Testing hypotheses about the relationship between cannabis use and psychosis." Drug Alcohol Depend 71(1): 37-48.
AIM: To model the impact of rising rates of cannabis use on the incidence and prevalence of psychosis under four hypotheses about the relationship between cannabis use and psychosis. METHODS: The study modelled the effects on the prevalence of schizophrenia over the lifespan of cannabis in eight birth cohorts: 1940-1944, 1945-1949, 1950-1954, 1955-1959, 1960-1964, 1965-1969, 1970-1974, 1975-1979. It derived predictions as to the number of cases of schizophrenia that would be observed in these birth cohorts, given the following four hypotheses: (1) that there is a causal relationship between cannabis use and schizophrenia; (2) that cannabis use precipitates schizophrenia in vulnerable persons; (3) that cannabis use exacerbates schizophrenia; and (4) that persons with schizophrenia are more liable to become regular cannabis users. RESULTS: There was a steep rise in the prevalence of cannabis use in Australia over the past 30 years and a corresponding decrease in the age of initiation of cannabis use. There was no evidence of a significant increase in the incidence of schizophrenia over the past 30 years. Data on trends the age of onset of schizophrenia did not show a clear pattern. Cannabis use among persons with schizophrenia has consistently been found to be more common than in the general population. CONCLUSIONS: Cannabis use does not appear to be causally related to the incidence of schizophrenia, but its use may precipitate disorders in persons who are vulnerable to developing psychosis and worsen the course of the disorder among those who have already developed it.

Denissenko, M. F., A. Pao, et al. (1996). "Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53." Science 274(5286): 430-2.
Cigarette smoke carcinogens such as benzo[a]pyrene are implicated in the development of lung cancer. The distribution of benzo[a]pyrene diol epoxide (BPDE) adducts along exons of the P53 gene in BPDE-treated HeLa cells and bronchial epithelial cells was mapped at nucleotide resolution. Strong and selective adduct formation occurred at guanine positions in codons 157, 248, and 273. These same positions are the major mutational hotspots in human lung cancers. Thus, targeted adduct formation rather than phenotypic selection appears to shape the P53 mutational spectrum in lung cancer. These results provide a direct etiological link between a defined chemical carcinogen and human cancer.

Drummer, O. H., J. Gerostamoulos, et al. (2004). "The involvement of drugs in drivers of motor vehicles killed in Australian road traffic crashes." Accid Anal Prev 36(2): 239-48.
A multi-center case-control study was conducted on 3398 fatally-injured drivers to assess the effect of alcohol and drug use on the likelihood of them being culpable. Crashes investigated were from three Australian states (Victoria, New South Wales and Western Australia). The control group of drug- and alcohol-free drivers comprised 50.1% of the study population. A previously validated method of responsibility analysis was used to classify drivers as either culpable or non-culpable. Cases in which the driver "contributed" to the crash (n=188) were excluded. Logistic regression was used to examine the association of key attributes such as age, gender, type of crash and drug use on the likelihood of culpability. Drivers positive to psychotropic drugs were significantly more likely to be culpable than drug-free drivers. Drivers with Delta(9)-tetrahydrocannabinol (THC) in their blood had a significantly higher likelihood of being culpable than drug-free drivers (odds ratio (OR) 2.7, 95% CI 1.02-7.0). For drivers with blood THC concentrations of 5 ng/ml or higher the odds ratio was greater and more statistically significant (OR 6.6, 95% CI 1.5-28.0). The estimated odds ratio is greater than that for drivers with a blood alcohol concentration (BAC) of 0.10-0.15% (OR 3.7, 95% CI 1.5-9.1). A significantly stronger positive association with culpability was seen with drivers positive to THC and with BAC > or =0.05% compared with BAC > or =0.05 alone (OR 2.9, 95% CI 1.1-7.7). Strong associations were also seen for stimulants, particularly in truck drivers. There were non-significant, weakly positive associations of opiates and benzodiazepines with culpability. Drivers positive to any psychoactive drug were significantly more likely to be culpable (OR 1.8, 95% CI 1.3-2.4). Gender differences were not significant, but differences were apparent with age. Drivers showing the highest culpability rates were in the under 25 and over 65 age groups.

Ellickson, P. L., S. C. Martino, et al. (2004). "Marijuana use from adolescence to young adulthood: multiple developmental trajectories and their associated outcomes." Health Psychol 23(3): 299-307.
This study used latent growth mixture modeling to identify discrete developmental patterns of marijuana use from early adolescence (age 13) to young adulthood (age 23) among a sample of 5,833 individuals. After the a priori removal of abstainers, 4 trajectory groups were identified: early high users, who decreased from a relatively high level of use at age 13 to a more moderate level: stable light users, who maintained a low level of use: steady increasers, who consistently increased use; and occasional light users, who began use at age 14 and used at low levels thereafter. Analyses of covariance comparing the trajectory groups on behavioral, socioeconomic, and health outcomes at age 29 revealed that abstainers consistently had the most favorable outcomes, whereas early high users consistently had the least favorable outcomes.

Fergusson, D. M., L. J. Horwood, et al. (2003). "Cannabis and educational achievement." Addiction 98(12): 1681-92.
AIMS: To examine the relationship between cannabis use in adolescence/young adulthood and levels of educational attainment. DESIGN: Data were gathered over the course of a 25-year longitudinal study of a birth cohort of 1265 New Zealand children. MEASUREMENTS: Measures analysed included (a) frequency of cannabis use in adolescence and young adulthood (15-25 years); (b) levels of educational achievement to age 25 years; and (c) social, family and individual characteristics assessed prior to age 16. FINDINGS: Increasing cannabis use was associated with increasing risks of leaving school without qualifications, failure to enter university and failure to obtain a university degree. The association between cannabis use and leaving school without qualifications persisted after control for confounding factors. When due allowance was made for pre-existing levels of cannabis use there was no evidence to suggest the presence of reverse causal pathways in which lower educational achievement led to increased cannabis use. CONCLUSIONS: Findings support the view that cannabis use may act to decrease educational achievement in young people. It is likely that this reflects the effects of the social context within which cannabis is used rather than any direct effect of cannabis on cognitive ability or motivation.

Fergusson, D. M., L. J. Horwood, et al. (2002). "Maternal use of cannabis and pregnancy outcome." BJOG 109(1): 21-7.
OBJECTIVE: To document the prevalence of cannabis use in a large sample of British women studied during pregnancy, to determine the association between cannabis use and social and lifestyle factors and assess any independent effects on pregnancy outcome. DESIGN: Self-completed questionnaire on use of cannabis before and during pregnancy. SAMPLE: Over 12,000 women expecting singletons at 18 to 20 weeks of gestation who were enrolled in the Avon Longitudinal Study of Pregnancy and Childhood. METHODS: Any association with the use of cannabis before and during pregnancy with pregnancy outcome was examined, taking into account potentially confounding factors including maternal social background and other substance use during pregnancy. MAIN OUTCOME MEASURES: Late fetal and perinatal death, special care admission of the newborn infant, birthweight, birth length and head circumference. RESULTS: Five percent of mothers reported smoking cannabis before and/or during pregnancy; they were younger, of lower parity, better educated and more likely to use alcohol, cigarettes, coffee, tea and hard drugs. Cannabis use during pregnancy was unrelated to risk of perinatal death or need for special care, but, the babies of women who used cannabis at least once per week before and throughout pregnancy were 216 g lighter than those of non-users, had significantly shorter birth lengths and smaller head circumferences. After adjustment for confounding factors, the association between cannabis use and birthweight failed to be statistically significant (P = 0.056) and was clearly non-linear: the adjusted mean birthweights for babies of women using cannabis at least once per week before and throughout