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

Fergusson, D. M., L. J. Horwood, et al. (2002). "Cannabis use and psychosocial adjustment in adolescence and young adulthood." Addiction 97(9): 1123-35.
AIM: To examine the associations between frequency of cannabis use and psychosocial outcomes in adolescence/young adulthood. DESIGN: A 21-year longitudinal study of the health, development and adjustment of a birth cohort of 1265 New Zealand children. MEASUREMENTS: Annual assessments of the frequency of cannabis use were obtained for the period from age 14-21 years, together with measures of psychosocial outcomes including property/violent crime, depression, suicidal ideation, suicide attempt and other illicit drug use. FINDINGS: The frequency of cannabis use was associated significantly with all outcomes, and particularly other illicit drug use. Statistical control for confounding by both fixed and time-dynamic factors substantially reduced the strength of association between cannabis use and outcome measures. Nevertheless, cannabis use remained significantly (P < 0.05) associated with all outcomes and particularly other illicit drug use, after adjustment for confounding. For the measures of crime, suicidal behaviours and other illicit drug use there was evidence of age related variation in the strength of association with cannabis use, with younger (14-15 years old) users being more affected by regular cannabis use than older (20-21 years old) regular users. However, the association between cannabis use and depression did not vary with age. CONCLUSIONS: Cannabis use, and particularly regular or heavy use, was associated with increased rates of a range of adjustment problems in adolescence/ young adulthood-other illicit drug use, crime, depression and suicidal behaviours-with these adverse effects being most evident for school-aged regular users. The findings reinforce public health concerns about minimizing the use of cannabis among school-aged populations.

Forrester, M. B. and R. D. Merz (2007). "Risk of selected birth defects with prenatal illicit drug use, Hawaii, 1986-2002." J Toxicol Environ Health A 70(1): 7-18.
The literature on the association between prenatal illicit drug use and birth defects is inconsistent. The objective of this study was to determine the risk of a variety of birth defects with prenatal illicit drug use. Data were derived from an active, population-based adverse pregnancy outcome registry. Cases were all infants and fetuses with any of 54 selected birth defects delivered during 1986-2002. The prenatal methamphetamine, cocaine, or marijuana use rates were calculated for each birth defect and compared to the prenatal use rates among all deliveries. Among all deliveries, the prenatal use rate was 0.52% for methamphetamine, 0.18% for cocaine, and 0.26% for marijuana. Methamphetamine rates were significantly higher than expected for 14 (26%) of the birth defects. Cocaine rates were significantly higher than expected for 13 (24%) of the birth defects. Marijuana rates were significantly higher than expected for 21 (39%) of the birth defects. Increased risk for the three drugs occurred predominantly among birth defects associated with the central nervous system, cardiovascular system, oral clefts, and limbs. There was also increased risk of marijuana use among a variety of birth defects associated with the gastrointestinal system. Prenatal uses of methamphetamine, cocaine, and marijuana are all associated with increased risk of a variety of birth defects. The affected birth defects are primarily associated with particular organ systems.

Goldschmidt, L., G. A. Richardson, et al. (2004). "Prenatal marijuana and alcohol exposure and academic achievement at age 10." Neurotoxicol Teratol 26(4): 521-32.
The effects of prenatal marijuana and alcohol exposure on school achievement at 10 years of age were examined. Women were interviewed about their substance use at the end of each trimester of pregnancy, at 8 and 18 months, and at 3, 6, 10, 14, and 16 years. The women were of lower socioeconomic status, high-school-educated, and light-to-moderate users of marijuana and alcohol. The sample was equally divided between Caucasian and African-American women. At the 10-year follow-up, the effects of prenatal exposure to marijuana or alcohol on the academic performance of 606 children were assessed. Exposure to one or more marijuana joints per day during the first trimester predicted deficits in Wide Range Achievement Test-Revised (WRAT-R) reading and spelling scores and a lower rating on the teachers' evaluations of the children's performance. This relation was mediated by the effects of first-trimester marijuana exposure on the children's depression and anxiety symptoms. Second-trimester marijuana use was significantly associated with reading comprehension and underachievement. Exposure to alcohol during the first and second trimesters of pregnancy predicted poorer teachers' ratings of overall school performance. Second-trimester binge drinking predicted lower reading scores. There was no interaction between prenatal marijuana and alcohol exposure. Each was an independent predictor of academic performance.

Grotenhermen, F., G. Leson, et al. (2007). "Developing limits for driving under cannabis." Addiction 102(12): 1910-7.
OBJECTIVE: Development of a rational and enforceable basis for controlling the impact of cannabis use on traffic safety. METHODS: An international working group of experts on issues related to drug use and traffic safety evaluated evidence from experimental and epidemiological research and discussed potential approaches to developing per se limits for cannabis. RESULTS: In analogy to alcohol, finite (non-zero) per se limits for delta-9-tetrahydrocannabinol (THC) in blood appear to be the most effective approach to separating drivers who are impaired by cannabis use from those who are no longer under the influence. Limited epidemiological studies indicate that serum concentrations of THC below 10 ng/ml are not associated with an elevated accident risk. A comparison of meta-analyses of experimental studies on the impairment of driving-relevant skills by alcohol or cannabis suggests that a THC concentration in the serum of 7-10 ng/ml is correlated with an impairment comparable to that caused by a blood alcohol concentration (BAC) of 0.05%. Thus, a suitable numerical limit for THC in serum may fall in that range. CONCLUSIONS: This analysis offers an empirical basis for a per se limit for THC that allows identification of drivers impaired by cannabis. The limited epidemiological data render this limit preliminary.

Gruber, S. A., J. Rogowska, et al. (2009). "Altered affective response in marijuana smokers: an FMRI study." Drug Alcohol Depend 105(1-2): 139-53.
More than 94 million Americans have tried marijuana, and it remains the most widely used illicit drug in the nation. Investigations of the cognitive effects of marijuana report alterations in brain function during tasks requiring executive control, including inhibition and decision-making. Endogenous cannabinoids regulate a variety of emotional responses, including anxiety, mood control, and aggression; nevertheless, little is known about smokers' responses to affective stimuli. The anterior cingulate and amygdala play key roles in the inhibition of impulsive behavior and affective regulation, and studies using PET and fMRI have demonstrated changes within these regions in marijuana smokers. Given alterations in mood and perception often observed in smokers, we hypothesized altered fMRI patterns of response in 15 chronic heavy marijuana smokers relative to 15 non-marijuana smoking control subjects during the viewing of masked happy and fearful faces. Despite no between-group differences on clinical or demographic measures, smokers demonstrated a relative decrease in both anterior cingulate and amygdalar activity during masked affective stimuli compared to controls, who showed relative increases in activation within these regions during the viewing of masked faces. Findings indicate that chronic heavy marijuana smokers demonstrate altered activation of frontal and limbic systems while viewing masked faces, consistent with autoradiographic studies reporting high CB-1 receptor density in these regions. These data suggest differences in affective processing in chronic smokers, even when stimuli are presented below the level of conscious processing, and underscore the likelihood that marijuana smokers process emotional information differently from those who do not smoke, which may result in negative consequences.

Hall, W. and L. Degenhardt (2009). "Adverse health effects of non-medical cannabis use." Lancet 374(9698): 1383-91.
For over two decades, cannabis, commonly known as marijuana, has been the most widely used illicit drug by young people in high-income countries, and has recently become popular on a global scale. Epidemiological research during the past 10 years suggests that regular use of cannabis during adolescence and into adulthood can have adverse effects. Epidemiological, clinical, and laboratory studies have established an association between cannabis use and adverse outcomes. We focus on adverse health effects of greatest potential public health interest-that is, those that are most likely to occur and to affect a large number of cannabis users. The most probable adverse effects include a dependence syndrome, increased risk of motor vehicle crashes, impaired respiratory function, cardiovascular disease, and adverse effects of regular use on adolescent psychosocial development and mental health.Hall, W., L. Degenhardt, et al. (2001). The health and psychological effects of cannabis use. N. D. a. A. R. Center. University of New South Wales, Commonwealth of Australia. Monograph Series No. 44.

Iversen, L. (2003). "Cannabis and the brain." Brain 126(Pt 6): 1252-70.
The active compound in herbal cannabis, Delta(9)-tetrahydrocannabinol, exerts all of its known central effects through the CB(1) cannabinoid receptor. Research on cannabinoid mechanisms has been facilitated by the availability of selective antagonists acting at CB(1) receptors and the generation of CB(1) receptor knockout mice. Particularly important classes of neurons that express high levels of CB(1) receptors are GABAergic interneurons in hippocampus, amygdala and cerebral cortex, which also contain the neuropeptides cholecystokinin. Activation of CB(1) receptors leads to inhibition of the release of amino acid and monoamine neurotransmitters. The lipid derivatives anandamide and 2-arachidonylglycerol act as endogenous ligands for CB(1) receptors (endocannabinoids). They may act as retrograde synaptic mediators of the phenomena of depolarization-induced suppression of inhibition or excitation in hippocampus and cerebellum. Central effects of cannabinoids include disruption of psychomotor behaviour, short-term memory impairment, intoxication, stimulation of appetite, antinociceptive actions (particularly against pain of neuropathic origin) and anti-emetic effects. Although there are signs of mild cognitive impairment in chronic cannabis users there is little evidence that such impairments are irreversible, or that they are accompanied by drug-induced neuropathology. A proportion of regular users of cannabis develop tolerance and dependence on the drug. Some studies have linked chronic use of cannabis with an increased risk of psychiatric illness, but there is little evidence for any causal link. The potential medical applications of cannabis in the treatment of painful muscle spasms and other symptoms of multiple sclerosis are currently being tested in clinical trials. Medicines based on drugs that enhance the function of endocannabinoids may offer novel therapeutic approaches in the future.

Kalant, H. (2004). "Adverse effects of cannabis on health: an update of the literature since 1996." Prog Neuropsychopharmacol Biol Psychiatry 28(5): 849-63.
Recent research has clarified a number of important questions concerning adverse effects of cannabis on health. A causal role of acute cannabis intoxication in motor vehicle and other accidents has now been shown by the presence of measurable levels of Delta(9)-tetrahydrocannabinol (THC) in the blood of injured drivers in the absence of alcohol or other drugs, by surveys of driving under the influence of cannabis, and by significantly higher accident culpability risk of drivers using cannabis. Chronic inflammatory and precancerous changes in the airways have been demonstrated in cannabis smokers, and the most recent case-control study shows an increased risk of airways cancer that is proportional to the amount of cannabis use. Several different studies indicate that the epidemiological link between cannabis use and schizophrenia probably represents a causal role of cannabis in precipitating the onset or relapse of schizophrenia. A weaker but significant link between cannabis and depression has been found in various cohort studies, but the nature of the link is not yet clear. A large body of evidence now demonstrates that cannabis dependence, both behavioral and physical, does occur in about 7-10% of regular users, and that early onset of use, and especially of weekly or daily use, is a strong predictor of future dependence. Cognitive impairments of various types are readily demonstrable during acute cannabis intoxication, but there is no suitable evidence yet available to permit a decision as to whether long-lasting or permanent functional losses can result from chronic heavy use in adults. However, a small but growing body of evidence indicates subtle but apparently permanent effects on memory, information processing, and executive functions, in the offspring of women who used cannabis during pregnancy. In total, the evidence indicates that regular heavy use of cannabis carries significant risks for the individual user and for the health care system.

Liguori, A., C. P. Gatto, et al. (2002). "Separate and combined effects of marijuana and alcohol on mood, equilibrium and simulated driving." Psychopharmacology (Berl) 163(3-4): 399-405.
RATIONALE: Marijuana and alcohol, when used separately and in combination, contribute to automobile accidents and failed sobriety tests of standing balance. However, the extent to which the drugs have additive effects on both of these measures is unknown. OBJECTIVES: This study was designed to compare directly the separate and combined effects of marijuana and alcohol on simulated emergency braking and dynamic posturography. METHODS: Twelve healthy subjects who regularly used both marijuana and alcohol completed nine test sessions in a counterbalanced within-subject design. Subjects drank a beverage (0, 0.25, or 0.5 g/kg alcohol) then smoked a cigarette (0, 1.75, or 3.33% THC). Testing began 2 min after smoking and was conducted within the ascending limb of the blood alcohol curve. RESULTS: The 0.5 g/kg alcohol dose significantly increased brake latency without affecting body sway. In contrast, the 3.3% THC dose increased body sway but did not affect brake latency. There were no additive drug effects on mood or behavior. CONCLUSIONS: Although field sobriety tests are often used to determine driving impairment, these results suggest that impaired balance following marijuana use may not coincide with slowed reaction time. Conversely, braking impairment from low doses of alcohol may not be revealed by tests of balance.

Liguori, A., C. P. Gatto, et al. (1998). "Effects of marijuana on equilibrium, psychomotor performance, and simulated driving." Behav Pharmacol 9(7): 599-609.
Delta-9-tetrahydrocannabinol (THC) is frequently found in the blood of drivers involved in automobile accidents, and marijuana use has been associated with impaired field sobriety test performance. The present study used a within-subject design to compare the effects of marijuana (0, 1.77, or 3.95% THC) on equilibrium and simulated driving. Ten marijuana users (seven men, three women) smoked one marijuana cigarette at the beginning of each session. Then 2 min later, they began a 60-min test battery that included subjective effects scales, a computerized test of body sway, a rapid judgment task and brake latency measurement in a driving simulator, critical flicker fusion (CFF), and a choice reaction time task (CRT). Self-report ratings of 'high' and 'drug potency' increased comparably following both active doses. The high, but not the low, dose significantly increased body sway. The high dose also marginally increased brake latency by a mean of 55 ms (P < 0.10), which is comparable to an increase in stopping distance of nearly 5 feet at 60 mph Judgment, CFF, and CRT scores did not differ across dose conditions. The equilibrium and brake latency data with 3.95% THC are similar to prior results in our laboratory in participants with breath alcohol concentrations near 0.05%.

MacCoun, R. J. (1993). "Drugs and the law: a psychological analysis of drug prohibition." Psychol Bull 113(3): 497-512.
There is an ongoing American policy debate about the appropriate legal status for psychoactive drugs. Prohibition, decriminalization, and legalization positions are all premised on assumptions about the behavioral effects of drug laws. What is actually known and not known about these effects is reviewed. Rational-choice models of legal compliance suggest that criminalization reduces use through restricted drug availability, increased drug prices, and the deterrent effect of the risk of punishment. Research on these effects illustrates the need for a more realistic perspective that acknowledges the limitations of human rationality and the importance of moral reasoning and informal social control factors. There are at least 7 different mechanisms by which the law influences drug use, some of which are unintended and counterproductive. This framework is used to explore the potential behavioral effects of decriminalization and legalization.

Marco, E. M., T. Rubino, et al. (2009). "Long-term consequences of URB597 administration during adolescence on cannabinoid CB1 receptor binding in brain areas." Brain Res 1257: 25-31.
Despite the alarming increment in the use and abuse of cannabis preparations among young people, little is known about possible long-term consequences of targeting the endocannabinoid system during the critical developmental period of adolescence. Therefore, we aimed to analyze possible long-lasting neurobiological consequences of enhancing endocannabinoid signalling during adolescence, by means of blocking anandamide (AEA) hydrolysis. Adolescent Wistar male rats were administered an inhibitor of AEA hydrolysis, i.e. URB597 (0, 0.1 or 0.5 mg/kg/day from postnatal days 38 to 43). The expression of brain cannabinoid receptor type 1 (CB1R) was then analyzed by [(3)H]CP-55,940 auto-radiographic binding at adulthood. Repeated URB597 administration during adolescence persistently modified CB1R binding in a region-dependent manner. A long-lasting decrease of CB1R binding levels was found in caudate-putamen, nucleus accumbens, ventral tegmental area and hippocampus, while an opposite increment was observed in the locus coeruleus. Present results provide evidence for long-lasting effects of adolescent URB597 administration. Activation of endocannabinoid transmission during the still plastic phase of adolescence may have implications for the maturational end-point of the endocannabinoid system itself, which could lead to permanent alterations in neuronal brain circuits and behavioural responses. Insights into the developmental trajectories of this neuromodulatory system may help us to better understand and prevent outcomes of neonatal and adolescent cannabis exposure.

Medina, K. L., B. J. Nagel, et al. "Abnormal cerebellar morphometry in abstinent adolescent marijuana users." Psychiatry Res 182(2): 152-9.
Functional neuroimaging data from adults have, in general, revealed frontocerebellar dysfunction associated with acute and chronic marijuana (MJ) use. The goal of this study was to characterize cerebellar volume in adolescent chronic MJ users following 1 month of monitored abstinence. Participants were MJ users (n=16) and controls (n=16) aged 16-18 years. Extensive exclusionary criteria included history of psychiatric or neurologic disorders. Drug use history, neuropsychological data, and structural brain scans were collected after 28 days of monitored abstinence. Trained research staff defined cerebellar volumes (including three cerebellar vermis lobes and both cerebellar hemispheres) on high-resolution T1-weighted magnetic resonance images. Adolescent MJ users demonstrated significantly larger inferior posterior (lobules VIII-X) vermis volume than controls, above and beyond effects of lifetime alcohol and other drug use, gender, and intracranial volume. Larger vermis volumes were associated with poorer executive functioning. Following 1 month of abstinence, adolescent MJ users had significantly larger posterior cerebellar vermis volumes than non-using controls. These greater volumes are suggested to be pathological based on linkage to poorer executive functioning. Longitudinal studies are needed to examine typical cerebellar development during adolescence and the influence of marijuana use.

Mehra, R., B. A. Moore, et al. (2006). "The association between marijuana smoking and lung cancer: a systematic review." Arch Intern Med 166(13): 1359-67.
BACKGROUND: The association between marijuana smoking and lung cancer is unclear, and a systematic appraisal of this relationship has yet to be performed. Our objective was to assess the impact of marijuana smoking on the development of premalignant lung changes and lung cancer. METHODS: Studies assessing the impact of marijuana smoking on lung premalignant findings and lung cancer were selected from MEDLINE, PSYCHLIT, and EMBASE databases according to the following predefined criteria: English-language studies of persons 18 years or older identified from 1966 to the second week of October 2005 were included if they were research studies (ie, not letters, reviews, editorials, or limited case studies), involved persons who smoked marijuana, and examined premalignant or cancerous changes in the lung. RESULTS: Nineteen studies met selection criteria. Studies that examined lung cancer risk factors or premalignant changes in the lung found an association of marijuana smoking with increased tar exposure, alveolar macrophage tumoricidal dysfunction, increased oxidative stress, and bronchial mucosal histopathologic abnormalities compared with tobacco smokers or nonsmoking controls. Observational studies of subjects with marijuana exposure failed to demonstrate significant associations between marijuana smoking and lung cancer after adjusting for tobacco use. The primary methodologic deficiencies noted include selection bias, small sample size, limited generalizability, overall young participant age precluding sufficient lag time for lung cancer outcome identification, and lack of adjustment for tobacco smoking. CONCLUSION: Given the prevalence of marijuana smoking and studies predominantly supporting biological plausibility of an association of marijuana smoking with lung cancer on the basis of molecular, cellular, and histopathologic findings, physicians should advise patients regarding potential adverse health outcomes until further rigorous studies are performed that permit definitive conclusions.

Mittleman, M. A., R. A. Lewis, et al. (2001). "Triggering myocardial infarction by marijuana." Circulation 103(23): 2805-9.
BACKGROUND: Marijuana use in the age group prone to coronary artery disease is higher than it was in the past. Smoking marijuana is known to have hemodynamic consequences, including a dose-dependent increase in heart rate, supine hypertension, and postural hypotension; however, whether it can trigger the onset of myocardial infarction is unknown. METHODS AND RESULTS: In the Determinants of Myocardial Infarction Onset Study, we interviewed 3882 patients (1258 women) with acute myocardial infarction an average of 4 days after infarction onset. We used the case-crossover study design to compare the reported use of marijuana in the hour preceding symptoms of myocardial infarction onset to its expected frequency using self-matched control data. Of the 3882 patients, 124 (3.2%) reported smoking marijuana in the prior year, 37 within 24 hours and 9 within 1 hour of myocardial infarction symptoms. Compared with nonusers, marijuana users were more likely to be men (94% versus 67%, P<0.001), current cigarette smokers (68% versus 32%, P<0.001), and obese (43% versus 32%, P=0.008). They were less likely to have a history of angina (12% versus 25%, P<0.001) or hypertension (30% versus 44%, P=0.002). The risk of myocardial infarction onset was elevated 4.8 times over baseline (95% confidence interval, 2.4 to 9.5) in the 60 minutes after marijuana use. The elevated risk rapidly decreased thereafter. CONCLUSIONS: Smoking marijuana is a rare trigger of acute myocardial infarction. Understanding the mechanism through which marijuana causes infarction may provide insight into the triggering of myocardial infarction by this and other, more common stressors.

Moore, T. H., S. Zammit, et al. (2007). "Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review." Lancet 370(9584): 319-28.
BACKGROUND: Whether cannabis can cause psychotic or affective symptoms that persist beyond transient intoxication is unclear. We systematically reviewed the evidence pertaining to cannabis use and occurrence of psychotic or affective mental health outcomes. METHODS: We searched Medline, Embase, CINAHL, PsycINFO, ISI Web of Knowledge, ISI Proceedings, ZETOC, BIOSIS, LILACS, and MEDCARIB from their inception to September, 2006, searched reference lists of studies selected for inclusion, and contacted experts. Studies were included if longitudinal and population based. 35 studies from 4804 references were included. Data extraction and quality assessment were done independently and in duplicate. FINDINGS: There was an increased risk of any psychotic outcome in individuals who had ever used cannabis (pooled adjusted odds ratio=1.41, 95% CI 1.20-1.65). Findings were consistent with a dose-response effect, with greater risk in people who used cannabis most frequently (2.09, 1.54-2.84). Results of analyses restricted to studies of more clinically relevant psychotic disorders were similar. Depression, suicidal thoughts, and anxiety outcomes were examined separately. Findings for these outcomes were less consistent, and fewer attempts were made to address non-causal explanations, than for psychosis. A substantial confounding effect was present for both psychotic and affective outcomes. INTERPRETATION: The evidence is consistent with the view that cannabis increases risk of psychotic outcomes independently of confounding and transient intoxication effects, although evidence for affective outcomes is less strong. The uncertainty about whether cannabis causes psychosis is unlikely to be resolved by further longitudinal studies such as those reviewed here. However, we conclude that there is now sufficient evidence to warn young people that using cannabis could increase their risk of developing a psychotic illness later in life.

Patton, G. C., C. Coffey, et al. (2002). "Cannabis use and mental health in young people: cohort study." BMJ 325(7374): 1195-8.
OBJECTIVE: To determine whether cannabis use in adolescence predisposes to higher rates of depression and anxiety in young adulthood. DESIGN: Seven wave cohort study over six years. SETTING: 44 schools in the Australian state of Victoria. PARTICIPANTS: A statewide secondary school sample of 1601 students aged 14-15 followed for seven years. MAIN OUTCOME MEASURE: Interview measure of depression and anxiety (revised clinical interview schedule) at wave 7. RESULTS: Some 60% of participants had used cannabis by the age of 20; 7% were daily users at that point. Daily use in young women was associated with an over fivefold increase in the odds of reporting a state of depression and anxiety after adjustment for intercurrent use of other substances (odds ratio 5.6, 95% confidence interval 2.6 to 12). Weekly or more frequent cannabis use in teenagers predicted an approximately twofold increase in risk for later depression and anxiety (1.9, 1.1 to 3.3) after adjustment for potential baseline confounders. In contrast, depression and anxiety in teenagers predicted neither later weekly nor daily cannabis use. CONCLUSIONS: Frequent cannabis use in teenage girls predicts later depression and anxiety, with daily users carrying the highest risk. Given recent increasing levels of cannabis use, measures to reduce frequent and heavy recreational use seem warranted.

Perkins, D. O., H. Gu, et al. (2005). "Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: a critical review and meta-analysis." Am J Psychiatry 162(10): 1785-804.
OBJECTIVE: The duration of untreated psychosis may influence response to treatment, reflecting a potentially malleable progressive pathological process. The authors reviewed the literature on the association of duration of untreated psychosis with symptom severity at first treatment contact and with treatment outcomes and conducted a meta-analysis examining these relationships. METHOD: English-language articles on duration of untreated psychosis published in peer-reviewed journals through July 2004 were reviewed. Studies that quantitatively assessed the duration of untreated psychosis; identified study subjects who met the criteria for nonaffective psychotic disorders at or close to first treatment; employed cross-sectional analyses of duration of untreated psychosis and of baseline symptoms, neurocognition, brain morphology, or functional measures or prospectively analyzed symptom change, response, or relapse; assessed psychopathology with clinician-rated instruments; and reported subjects' diagnoses (a total of 43 publications from 28 sites) were included in the meta-analysis. RESULTS: Shorter duration of untreated psychosis was associated with greater response to antipsychotic treatment, as measured by severity of global psychopathology, positive symptoms, negative symptoms, and functional outcomes. At the time of treatment initiation, duration of initially untreated psychosis was associated with the severity of negative symptoms but not with the severity of positive symptoms, general psychopathology, or neurocognitive function. CONCLUSIONS: Duration of untreated psychosis may be a potentially modifiable prognostic factor. Understanding the mechanism by which duration of untreated psychosis influences prognosis may lead to better understanding of the pathophysiology of schizophrenia and to improved treatment strategies.

Quickfall, J. and D. Crockford (2006). "Brain neuroimaging in cannabis use: a review." J Neuropsychiatry Clin Neurosci 18(3): 318-32.
In this study, the authors systematically reviewed structural and functional neuroimaging studies of cannabis use. Structural abnormalities generally have not been identified with chronic use. Regular users demonstrate reciprocal changes in brain activity globally and in cerebellar and frontal regions. Abstinence results in decreases, and administration results in increases correlating with subjective intoxication. Chronic use and cannabis administration result in attenuated brain activity in task-activated regions or activation of compensatory regions. Findings correlate partially with neuropsychological data, but generalization is limited by the lack of use of diagnostic criteria, appropriately paired neuropsychological testing or means to better quantify cannabis use and abstinence.

Rais, M., W. Cahn, et al. (2008). "Excessive brain volume loss over time in cannabis-using first-episode schizophrenia patients." Am J Psychiatry 165(4): 490-6.
OBJECTIVE: Cerebral gray matter volume reductions have been found to progress over time in schizophrenia, with larger decreases related to poorer outcome, which has also been associated with cannabis use in schizophrenia patients. Progressive gray matter changes in patients who use cannabis may be more extensive than in those who do not. METHOD: Patients with recent-onset schizophrenia (N=51) and matched healthy subjects (N=31) were included. For all subjects, magnetic resonance imaging scans were obtained at inclusion (T0) and at 5-year follow-up (T5). Nineteen patients used cannabis but no other illicit drugs; 32 patients did not use any drugs during the 5-year follow-up. At T5, clinical outcome was measured. Cumulative amount of antipsychotic medication during the interval was calculated. At T0 and T5, total brain, gray and white matter, and lateral and third ventricle volumes were measured. Univariate analysis of covariance and pairwise comparisons were performed. Result: Schizophrenia patients showed a larger gray matter volume decrease over time than healthy subjects. They also showed larger increases in lateral and third ventricle volumes than healthy subjects and patients who did not use cannabis during follow-up. This decrement was significantly more pronounced in the patients who continued to use cannabis. These differences could not be attributed to outcome or baseline characteristics. CONCLUSIONS: First-episode schizophrenia patients who use cannabis show a more pronounced brain volume reduction over a 5-year follow-up than patients with schizophrenia who do not use cannabis. These results may help explain some of the detrimental effects of cannabis use in schizophrenia.

Ramaekers, J. G., G. Berghaus, et al. (2004). "Dose related risk of motor vehicle crashes after cannabis use." Drug Alcohol Depend 73(2): 109-19.
The role of Delta(9)-tetrahydrocannabinol (THC) in driver impairment and motor vehicle crashes has traditionally been established in experimental and epidemiological studies. Experimental studies have repeatedly shown that THC impairs cognition, psychomotor function and actual driving performance in a dose related manner. The degree of performance impairment observed in experimental studies after doses up to 300 microg/kg THC were equivalent to the impairing effect of an alcohol dose producing a blood alcohol concentration (BAC) >/=0.05 g/dl, the legal limit for driving under the influence in most European countries. Higher doses of THC, i.e. >300 microg/kg THC have not been systematically studied but can be predicted to produce even larger impairment. Detrimental effects of THC were more prominent in certain driving tasks than others. Highly automated behaviors, such as road tracking control, were more affected by THC as compared to more complex driving tasks requiring conscious control. Epidemiological findings on the role of THC in vehicle crashes have sometimes contrasted findings from experimental research. Case-control studies generally confirmed experimental data, but culpability surveys showed little evidence that crashed drivers who only used cannabis are more likely to cause accidents than drug free drivers. However, most culpability surveys have established cannabis use among crashed drivers by determining the presence of an inactive metabolite of THC in blood or urine that can be detected for days after smoking and can only be taken as evidence for past use of cannabis. Surveys that established recent use of cannabis by directly measuring THC in blood showed that THC positives, particularly at higher doses, are about three to seven times more likely to be responsible for their crash as compared to drivers that had not used drugs or alcohol. Together these epidemiological data suggests that recent use of cannabis may increase crash risk, whereas past use of cannabis does not. Experimental and epidemiological research provided similar findings concerning the combined use of THC and alcohol in traffic. Combined use of THC and alcohol produced severe impairment of cognitive, psychomotor, and actual driving performance in experimental studies and sharply increased the crash risk in epidemiological analyses.

Romero, J., E. Garcia-Palomero, et al. (1997). "Effects of chronic exposure to delta9-tetrahydrocannabinol on cannabinoid receptor binding and mRNA levels in several rat brain regions." Brain Res Mol Brain Res 46(1-2): 100-8.
Previous data showed the development of tolerance to a variety of pharmacological effects of plant and synthetic cannabinoids when administered chronically. This tolerance phenomenon has been related both to enhancement of cannabinoid metabolism and, in particular, to down-regulation of brain CB1 cannabinoid receptors, although this has been only demonstrated in extrapyramidal areas. In the present study, we have tested, by using autoradiographic analysis of CB1 receptor binding combined with analysis of CB1 receptor mRNA levels in specific brain regions by Northern blot, whether the reduction in binding levels of CB1 receptors observed in extrapyramidal areas after a chronic exposure to delta9-tetrahydrocannabinol (delta9-THC), also occurs in most brain areas that contain these receptors. Results were as follows. The acute exposure to delta9-THC usually resulted in no changes in the specific binding of CB1 receptors in all brain areas studied, discarding a possible interference in binding kinetic of the pre-bound administered drug. The only exceptions were the substantia nigra pars reticulata and the cerebral cortex, which exhibited decreased specific binding after the acute treatment with delta9-THC presumably due to an effect of the pre-bound drug. The specific binding measured in animals chronically (5 days) exposed to delta9-THC decreased ranging from approximately 20 up to 60% of the specific binding measured in control animals in all brain areas. Areas studied included cerebellum (molecular layer), hippocampus (CA1, CA2, CA3, CA4 and dentate gyrus), basal ganglia (medial and lateral caudate-putamen and substantia nigra pars reticulata), limbic nuclei (nucleus accumbens, septum nucleus and basolateral amygdaloid nucleus), superficial (CxI) and deep (CxVI) layers of the cerebral cortex and others. There were only two brain regions, the globus pallidus and the entopeduncular nucleus, where the specific binding for CB receptors was unaltered after 5 days of a daily delta9-THC administration. In addition, we have analyzed the levels of CB1 receptor mRNA in specific brain regions of animals chronically exposed to delta9-THC, in order to correlate them with changes in CB1 receptor binding. Thus, we observed a significant increase in CB1 receptor mRNA levels, but only in the striatum, with no changes in the hippocampus and cerebellum. In summary, CB1 receptor binding decreases after chronic delta9-THC exposure in most of the brain regions studied, although this was not accompanied by parallel decreases in CB receptor mRNA levels. This might indicate that the primary action of delta9-THC would be on the receptor protein itself rather than on the expression of CB1 receptor gene. In this context, the increase observed in mRNA amounts for this receptor in the striatum should be interpreted as a presumably compensatory effect to the reduction in binding levels observed in striatal outflow nuclei.

Scallet, A. C., E. Uemura, et al. (1987). "Morphometric studies of the rat hippocampus following chronic delta-9-tetrahydrocannabinol (THC)." Brain Res 436(1): 193-8.
Persistent behavioral effects resembling those of hippocampal brain lesions have been reported following chronic administration of marijuana or its major psychoactive constituent, delta-9-tetrahydrocannabinol (THC) to rats. We used morphometric techniques to investigate the effects of chronic THC on the anatomical integrity of the hippocampus. Rats dosed orally for 90 days with 10 to 60 mg/kg THC or vehicle were evaluated by light and electron microscopy up to 7 months after their last dose of drug. Electron micrographs revealed a striking ultrastructural appearance and statistically significant decreases in mean volume of neurons and their nuclei sampled from the hippocampal CA3 region of rats treated with the highest doses of THC. A 44% reduction in the number of synapses per unit volume was demonstrated in these same rats. Golgi impregnation studies of additional groups of rats treated with 10 or 20 mg/kg/day THC and sacrificed 2 months after their last treatment with THC revealed a reduction in the dendritic length of CA3 pyramidal neurons, despite normal appearing ultrastructure and no changes in synaptic density. The hippocampal changes reported here may constitute a morphological basis for behavioral effects after chronic exposure to marijuana.

Schuel, H. (2006). "Tuning the oviduct to the anandamide tone." J Clin Invest 116(8): 2087-90.
Anandamide (N-arachidonoylethanolamide) is a lipid signal molecule that was the first endogenous agonist for cannabinoid receptors to be discovered. Cannabinoid receptor type 1 (CB1) is widely distributed in neurons and nonneuronal cells in brain and peripheral organs including sperm, eggs, and preimplantation embryos. A study by Wang and colleagues in this issue of the JCI demonstrates that a critical balance between anandamide synthesis by N-acylphosphatidylethanolamine-selective phospholipase D (NAPE-PLD) and its degradation by fatty acid amide hydrolase (FAAH) in mouse embryos and oviducts creates locally an appropriate "anandamide tone" required for normal embryo development, oviductal transport, implantation, and pregnancy (see the related article beginning on page 2122). Adverse effects of elevated levels of anandamide on these processes resulting from FAAH inactivation are mimicked by administration of (-)-Delta9-tetrahydrocannabinol (THC; the major psychoactive constituent of marijuana), due to enhanced signaling via CB1. These findings show that exogenous THC can swamp endogenous anandamide signaling systems, thereby affecting multiple physiological processes.

Schweinsburg, A. D., S. A. Brown, et al. (2008). "The influence of marijuana use on neurocognitive functioning in adolescents." Curr Drug Abuse Rev 1(1): 99-111.
Marijuana use is common in adolescence, yet neural consequences have not been well delineated. This review seeks to ascertain whether heavy marijuana use in adolescence is associated with persistent neurocognitive abnormalities, and whether adolescents are more vulnerable to the impact of chronic marijuana use than adults. Among heavy marijuana using adults, neurocognitive deficits are apparent for several days following use, but may disappear after one month of abstinence. Studies of adolescent heavy users have identified impairments in learning and working memory up to six weeks after cessation, suggesting persisting effects, yet raise the possibility that abnormalities may remit with a longer duration of abstinence. Given ongoing neuromaturation during youth, adolescents may be more vulnerable to potential consequences of marijuana use than adults. This is supported by rodent models, which show greater memory impairments in animals exposed to cannabinoids as adolescents relative to those exposed as adults. Further, adult humans who initiated use in early adolescence show greater dysfunction than those who began use later. Together, these results suggest that adolescents are more vulnerable than adults to neurocognitive abnormalities associated with chronic heavy marijuana use; however, the impact of preexisting risk factors is unknown. Adolescents demonstrate persisting deficits related to heavy marijuana use for at least six weeks following discontinuation, particularly in the domains of learning, memory, and working memory. Further, adolescents appear more adversely affected by heavy use than adults. Longitudinal studies will help ascertain whether preexisting differences contribute to these abnormalities.

Solowij, N., R. S. Stephens, et al. (2002). "Cognitive functioning of long-term heavy cannabis users seeking treatment." JAMA 287(9): 1123-31.
CONTEXT: Cognitive impairments are associated with long-term cannabis use, but the parameters of use that contribute to impairments and the nature and endurance of cognitive dysfunction remain uncertain. OBJECTIVE: To examine the effects of duration of cannabis use on specific areas of cognitive functioning among users seeking treatment for cannabis dependence. DESIGN, SETTING, AND PARTICIPANTS: Multisite retrospective cross-sectional neuropsychological study conducted in the United States (Seattle, Wash; Farmington, Conn; and Miami, Fla) between 1997 and 2000 among 102 near-daily cannabis users (51 long-term users: mean, 23.9 years of use; 51 shorter-term users: mean, 10.2 years of use) compared with 33 nonuser controls. MAIN OUTCOME MEASURES: Measures from 9 standard neuropsychological tests that assessed attention, memory, and executive functioning, and were administered prior to entry to a treatment program and following a median 17-hour abstinence. RESULTS: Long-term cannabis users performed significantly less well than shorter-term users and controls on tests of memory and attention. On the Rey Auditory Verbal Learning Test, long-term users recalled significantly fewer words than either shorter-term users (P =.001) or controls (P =.005); there was no difference between shorter-term users and controls. Long-term users showed impaired learning (P =.007), retention (P =.003), and retrieval (P =.002) compared with controls. Both user groups performed poorly on a time estimation task (P<.001 vs controls). Performance measures often correlated significantly with the duration of cannabis use, being worse with increasing years of use, but were unrelated to withdrawal symptoms and persisted after controlling for recent cannabis use and other drug use. CONCLUSIONS: These results confirm that long-term heavy cannabis users show impairments in memory and attention that endure beyond the period of intoxication and worsen with increasing years of regular cannabis use.

Steiner, M. A. and C. T. Wotjak (2008). "Role of the endocannabinoid system in regulation of the hypothalamic-pituitary-adrenocortical axis." Prog Brain Res 170: 397-432.
The endocannabinoid system has been recognized as a major neuromodulatory system, which functions to maintain brain homoeostasis. Endocannabinoids are synthesized and released from the postsynapse and act as retrograde neuronal messengers, which bind to cannabinoid type 1 receptors at the presynapse. Here, they inhibit the release of neurotransmitters, including glutamate and GABA. By these means, endocannabinoids control the activation of various neuronal circuits including those involved in neuroendocrine stress processing. Accordingly, exogenous cannabinoids such as the major active component of marijuana, Delta(9)-tetrahydrocannabinol, have long been known to activate the major neuroendocrine stress response system of mammals, the hypothalamic-pituitary-adrenocortical (HPA) axis. However, the function of the endocannabinoid system in the regulation of stress hormone secretion has only recently begun to be understood. It is the focus of the present review to provide the reader with an overview of our current knowledge of the role of endocannabinoid signalling in HPA axis regulation under basal as well as under stressful conditions. This includes the specific sites of action, potential underlying neuronal pathways and interactions between behavioural and neuroendocrine stress coping. Furthermore, the potential role of HPA axis activity dysregulations, caused by deficits in the endocannabinoid system, for the pathophysiology of psychiatric diseases is discussed.

Tapert, S. F., A. D. Schweinsburg, et al. (2007). "Functional MRI of inhibitory processing in abstinent adolescent marijuana users." Psychopharmacology (Berl) 194(2): 173-83.
BACKGROUND: Marijuana intoxication appears to impair response inhibition, but it is unclear if impaired inhibition and associated brain abnormalities persist after prolonged abstinence among adolescent users. We hypothesized that brain activation during a go/no-go task would show persistent abnormalities in adolescent marijuana users after 28 days of abstinence. METHODS: Adolescents with (n = 16) and without (n = 17) histories of marijuana use were compared on blood oxygen level dependent (BOLD) response to a go/no-go task during functional magnetic resonance imaging (fMRI) after 28 days of monitored abstinence. Participants had no neurological problems or Axis I diagnoses other than cannabis abuse/dependence. RESULTS: Marijuana users did not differ from non-users on task performance but showed more BOLD response than non-users during inhibition trials in right dorsolateral prefrontal, bilateral medial frontal, bilateral inferior and superior parietal lobules, and right occipital gyri, as well as during "go" trials in right prefrontal, insular, and parietal cortices (p < 0.05, clusters > 943 microl). Differences remained significant even after controlling for lifetime and recent alcohol use. CONCLUSIONS: Adolescent marijuana users relative to non-users showed increased brain processing effort during an inhibition task in the presence of similar task performance, even after 28 days of abstinence. Thus, increased brain processing effort to achieve inhibition may predate the onset of regular use or result from it. Future investigations will need to determine whether increased brain processing effort is associated with risk to use.

Tashkin, D. P., G. C. Baldwin, et al. (2002). "Respiratory and immunologic consequences of marijuana smoking." J Clin Pharmacol 42(11 Suppl): 71S-81S.
Habitual smoking of marijuana has a number of effects on the respiratory and immune systems that may be clinically relevant. These include alterations in lung function ranging from no to mild airflow obstruction without evidence of diffusion impairment, an increased prevalence of acute and chronic bronchitis, striking endoscopic findings of airway injury (erythema, edema, and increased secretions) that correlate with histopathological alterations in bronchial biopsies, and dysregulated growth of the bronchial epithelium associated with altered expression of nuclear and cytoplasmic proteins involved in the pathogenesis of bronchogenic carcinoma. Other consequences of regular marijuana use include ultrastructual abnormalities in human alveolar macrophages along with impairment of their cytokine production, antimicrobial activity, and tumoricidal function. Cannabinoid receptor expression is altered in leukocytes collected from the blood of chronic smokers, and experimental models support a role for delta9-tetrahydrocannabinol in suppressing T cell function and cell-mediated immunity. The potential for marijuana smoking to predispose to the development of respiratory malignancy is suggested by several lines of evidence, including the presence of potent carcinogens in marijuana smoke and their resulting deposition in the lung, the occurrence of premalignant changes in bronchial biopsies obtained from smokers of marijuana in the absence of tobacco, impairment of antitumor immune defenses by delta9-tetrahydrocannabinol, and several clinical case series in which marijuana smokers were disproportionately over represented among young individuals who developed upper or lower respiratory tract cancer. Additional well designed epidemiological and immune monitoring studies are required to determine the potential causal relationship between marijuana use and the development of respiratory infection and/or cancer.

Taylor, D. R., D. M. Fergusson, et al. (2002). "A longitudinal study of the effects of tobacco and cannabis exposure on lung function in young adults." Addiction 97(8): 1055-61.
AIM: To assess the possible effects of tobacco and cannabis smoking on lung function in young adults between the ages of 18 and 26. SETTING AND PARTICIPANTS: A group of over 900 young adults derived from a birth cohort of 1037 subjects born in Dunedin, New Zealand in 1972/73 were studied at age 18, 21 and 26 years. MEASUREMENTS: Cannabis and tobacco smoking were documented at each age using a standardized interview. Lung function, as measured by the forced expiratory volume in one second/vital capacity (FEV1/VC) ratio, was obtained by simple spirometry. A fixed effects regression model was used to analyse the data to take account of confounding factors. FINDINGS: When the sample was stratified for cumulative use, there was evidence of a linear relationship between cannabis use and FEV1/VC (P < 0.05). In the absence of adjusting for other variables, increasing cannabis use over time was associated with a decline in FEV1/VC with time; the mean FEV1/VC among subjects using cannabis on 900 or more occasions was 7.2%, 2.6% and 5.0% less than non-users at ages 18, 21 and 26, respectively. After controlling for potential confounding factors (age, tobacco smoking and weight) the negative effect of cumulative cannabis use on mean FEV1/VC was only marginally significant (P < 0.09). Age (P < 0.001), cigarette smoking (P < 0.05) and weight (P < 0.001) were all significant predictors of FEV1/VC. Cannabis use and daily cigarette smoking acted additively to influence FEV1/VC. CONCLUSIONS: Longitudinal observations over 8 years in young adults revealed a dose-dependent relationship between cumulative cannabis consumption and decline in FEV1/VC. However, when confounders were accounted for the effect was reduced and was only marginally significant, but given the limited time frame over which observations were made, the trend suggests that continued cannabis smoking has the potential to result in clinically important impairment of lung function.

Terry, P. and K. A. Wright (2005). "Self-reported driving behaviour and attitudes towards driving under the influence of cannabis among three different user groups in England." Addict Behav 30(3): 619-26.
The study characterized self-reported driving behaviour, attitudes towards driving and assumptions about the effects of cannabis on driving, among two different volunteer groups: 63 regular cannabis users (RCUs; cannabis use>monthly) and 46 undergraduate student users, all from the West Midlands. More detailed information was provided by structured interviews with an additional sample of 23 regular users from southern England. Within each group, many respondents had driven whilst under the influence of cannabis (regular users, 82%; students, 40%; interviewees, 100%). Majorities among the regular users and interviewees continued to do so at least monthly. Most users believed that cannabis impaired driving only slightly. More stops by the police for drug-driving than for drink-driving were reported, but these rarely resulted in conviction and were not deterrent. Hence, cannabis users are very willing to drive after using the drug (often combined with alcohol), and even while intoxicated. They consider its effects on driving to be minimal; indeed, many consider it to promote better driving. Attitudes towards drink-driving were much more negative. Finally, most interviewees said that roadside drug testing would be the only efficacious deterrent to drug-driving.

Wadsworth, E. J., S. C. Moss, et al. (2006). "Cannabis use, cognitive performance and mood in a sample of workers." J Psychopharmacol 20(1): 14-23.
There are well documented acute and chronic effects of cannabis use on mental functioning. However, less is known about any effects on cognition within the context of work and everyday life. The aim of the study was to examine any association between cannabis use and cognitive performance, mood and human error at work. Cannabis users and controls completed a battery of laboratory based computer tasks measuring mood and cognitive function pre- and post-work at the start and end of a working week. They also completed daily diaries reporting their work performance. Cannabis use was associated with impairment in both cognitive function and mood, though cannabis users reported no more workplace errors than controls. Cannabis use was associated with lower alertness and slower response organization. In addition, users experienced working memory problems at the start, and psychomotor slowing and poorer episodic recall at the end of the working week. This pattern of results suggests two possible effects. First a 'hangover'-type effect which may increase with frequency of use. Second a subtle effect on cognitive function, perhaps more apparent under cognitive load and/or fatigue, which may increase with more prolonged use. The results also highlight the importance of the timing of testing within the context and routine of everyday life.

Wang, H., Y. Guo, et al. (2004). "Aberrant cannabinoid signaling impairs oviductal transport of embryos." Nat Med 10(10): 1074-80.
Ectopic pregnancy is a major reproductive health issue. Although other underlying causes remain largely unknown, one cause of ectopic pregnancy is embryo retention in the fallopian tube. Here we show that genetic or pharmacologic silencing of cannabinoid receptor CB1 causes retention of a large number of embryos in the mouse oviduct, eventually leading to pregnancy failure. This is reversed by isoproterenol, a beta-adrenergic receptor agonist. Impaired oviductal embryo transport is also observed in wild-type mice treated with methanandamide. Collectively, the results suggest that aberrant cannabinoid signaling impedes coordinated oviductal smooth muscle contraction and relaxation crucial to normal oviductal embryo transport. Colocalization of CB1 and beta2-adrenergic receptors in the oviduct muscularis implies that a basal endocannabinoid tone in collaboration with adrenergic receptors coordinates oviductal motility for normal journey of embryos into the uterus. Besides uncovering a new regulatory mechanism, this study could be clinically relevant to ectopic pregnancy.

Wang, H., H. Xie, et al. (2006). "Fatty acid amide hydrolase deficiency limits early pregnancy events." J Clin Invest 116(8): 2122-31.
Synchronized preimplantation embryo development and passage through the oviduct into the uterus are prerequisites for implantation, dysregulation of which often leads to pregnancy failure in women. Cannabinoid/endocannabinoid signaling via cannabinoid receptor CB1 is known to influence early pregnancy. Here we provide evidence that a critical balance between anandamide synthesis by N-acylphosphatidylethanolamine-selective phospholipase D (NAPE-PLD) and its degradation by fatty acid amide hydrolase (FAAH) in mouse embryos and oviducts creates locally an appropriate "anandamide tone" for normal development of embryos and their oviductal transport. FAAH inactivation yielding higher anandamide or experimentally induced higher cannabinoid [(-)-Delta9-tetrahydrocannabinol] levels constrain preimplantation embryo development with aberrant expression of Cdx2, Nanog, and Oct3/4, genes known to direct lineage specification. Defective oviductal embryo transport arising from aberrant endocannabinoid signaling also led to deferred on-time implantation and poor pregnancy outcome. Intercrossing between wild-type and Faah-/- mice rescued developmental defects, not oviductal transport, implying that embryonic and maternal FAAH plays differential roles in these processes. The results suggest that FAAH is a key metabolic gatekeeper, regulating on-site anandamide tone to direct preimplantation events that determine the fate of pregnancy. This study uncovers what we believe to be a novel regulation of preimplantation processes, which could be clinically relevant for fertility regulation in women.

Yucel, M., N. Solowij, et al. (2008). "Regional brain abnormalities associated with long-term heavy cannabis use." Arch Gen Psychiatry 65(6): 694-701.
CONTEXT: Cannabis is the most widely used illicit drug in the developed world. Despite this, there is a paucity of research examining its long-term effect on the human brain. OBJECTIVE: To determine whether long-term heavy cannabis use is associated with gross anatomical abnormalities in 2 cannabinoid receptor-rich regions of the brain, the hippocampus and the amygdala. DESIGN: Cross-sectional design using high-resolution (3-T) structural magnetic resonance imaging. SETTING: Participants were recruited from the general community and underwent imaging at a hospital research facility. PARTICIPANTS: Fifteen carefully selected long-term (>10 years) and heavy (>5 joints daily) cannabis-using men (mean age, 39.8 years; mean duration of regular use, 19.7 years) with no history of polydrug abuse or neurologic/mental disorder and 16 matched nonusing control subjects (mean age, 36.4 years). MAIN OUTCOME MEASURES: Volumetric measures of the hippocampus and the amygdala combined with measures of cannabis use. Subthreshold psychotic symptoms and verbal learning ability were also measured. RESULTS: Cannabis users had bilaterally reduced hippocampal and amygdala volumes (P = .001), with a relatively (and significantly [P = .02]) greater magnitude of reduction in the former (12.0% vs 7.1%). Left hemisphere hippocampal volume was inversely associated with cumulative exposure to cannabis during the previous 10 years (P = .01) and subthreshold positive psychotic symptoms (P < .001). Positive symptom scores were also associated with cumulative exposure to cannabis (P = .048). Although cannabis users performed significantly worse than controls on verbal learning (P < .001), this did not correlate with regional brain volumes in either group. CONCLUSIONS: These results provide new evidence of exposure-related structural abnormalities in the hippocampus and amygdala in long-term heavy cannabis users and corroborate similar findings in the animal literature. These findings indicate that heavy daily cannabis use across protracted periods exerts harmful effects on brain tissue and mental health.

Zhang, Z. F., H. Morgenstern, et al. (1999). "Marijuana use and increased risk of squamous cell carcinoma of the head and neck." Cancer Epidemiol Biomarkers Prev 8(12): 1071-8.
Marijuana is the most commonly used illegal drug in the United States. In some subcultures, it is widely perceived to be harmless. Although the carcinogenic properties of marijuana smoke are similar to those of tobacco, no epidemiological studies of the relationship between marijuana use and head and neck cancer have been published. The relationship between marijuana use and head and neck cancer was investigated by a case-control study of 173 previously untreated cases with pathologically confirmed diagnoses of squamous cell carcinoma of the head and neck and 176 cancer-free controls at Memorial Sloan-Kettering Cancer Center between 1992 and 1994. Epidemiological data were collected by using a structured questionnaire, which included history of tobacco smoking, alcohol use, and marijuana use. The associations between marijuana use and head and neck cancer were analyzed by Mantel-Haenszel methods and logistic regression models. Controlling for age, sex, race, education, alcohol consumption, pack-years of cigarette smoking, and passive smoking, the risk of squamous cell carcinoma of the head and neck was increased with marijuana use [odds ratio (OR) comparing ever with never users, 2.6; 95% confidence interval (CI), 1.1-6.6]. Dose-response relationships were observed for frequency of marijuana use/day (P for trend <0.05) and years of marijuana use (P for trend <0.05). These associations were stronger for subjects who were 55 years of age and younger (OR, 3.1; 95% CI, 1.0-9.7). Possible interaction effects of marijuana use were observed with cigarette smoking, mutagen sensitivity, and to a lesser extent, alcohol use. Our results suggest that marijuana use may increase the risk of head and neck cancer with a strong dose-response pattern. Our analysis indicated that marijuana use may interact with mutagen sensitivity and other risk factors to increase the risk of head and neck cancer. The results need to be interpreted with some caution in drawing causal inferences because of certain methodological limitations, especially with regard to interactions.