ArticlePDF AvailableLiterature Review
new england journal
n engl j med 370;23 june 5, 2014
Dan L. Longo, M.D., Editor
review article
Adverse Health Effects of Marijuana Use
Nora D. Volkow, M.D., Ruben D. Baler, Ph.D., Wilson M. Compton, M.D.,
and Susan R.B. Weiss, Ph.D.
From the National Institute on Drug
Abuse, National Institutes of Health,
Bethesda, MD. Address reprint requests
to Dr. Volkow at the National Institute
on Drug Abuse, 6001 Executive Blvd.,
Rm. 5274, Bethesda, MD 20892, or at
N Engl J Med 2014;370:2219-27.
DOI: 10.1056/NEJMra1402309
Copyright © 2014 Massachusetts Medical Society.
n light of the rapidly shifting landscape regarding the legaliza-
tion of marijuana for medical and recreational purposes, patients may be more
likely to ask physicians about its potential adverse and beneficial effects on
health. The popular notion seems to be that marijuana is a harmless pleasure, ac-
cess to which should not be regulated or considered illegal. Currently, marijuana is
the most commonly used “illicit” drug in the United States, with about 12% of
people 12 years of age or older reporting use in the past year and particularly high
rates of use among young people.
The most common route of administration is
inhalation. The greenish-gray shredded leaves and flowers of the Cannabis sativa
plant are smoked (along with stems and seeds) in cigarettes, cigars, pipes, water
pipes, or “blunts” (marijuana rolled in the tobacco-leaf wrapper from a cigar).
Hashish is a related product created from the resin of marijuana flowers and is
usually smoked (by itself or in a mixture with tobacco) but can be ingested orally.
Marijuana can also be used to brew tea, and its oil-based extract can be mixed into
food products.
The regular use of marijuana during adolescence is of particular concern, since
use by this age group is associated with an increased likelihood of deleterious
(Table 1). Although multiple studies have reported detrimental ef-
fects, others have not, and the question of whether marijuana is harmful remains
the subject of heated debate. Here we review the current state of the science re-
lated to the adverse health effects of the recreational use of marijuana, focusing
on those areas for which the evidence is strongest.
Adverse Effects
Risk of Addiction
Despite some contentious discussions regarding the addictiveness of marijuana,
the evidence clearly indicates that long-term marijuana use can lead to addiction.
Indeed, approximately 9% of those who experiment with marijuana will become
addicted3 (according to the criteria for dependence in the Diagnostic and Statistical
Manual of Mental Disorders, 4th edition [DSM-IV]). The number goes up to about 1 in
6 among those who start using marijuana as teenagers and to 25 to 50% among
those who smoke marijuana daily.4 According to the 2012 National Survey on Drug
Use and Health, an estimated 2.7 million people 12 years of age and older met the
DSM-IV criteria for dependence on marijuana, and 5.1 million people met the crite-
ria for dependence on any illicit drug1 (8.6 million met the criteria for dependence
on alcohol1). There is also recognition of a bona fide cannabis withdrawal syn-
drome5 (with symptoms that include irritability, sleeping difficulties, dysphoria,
craving, and anxiety), which makes cessation difficult and contributes to relapse.
Marijuana use by adolescents is particularly troublesome. Adolescents’ increased
vulnerability to adverse long-term outcomes from marijuana use is probably related
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new england journal
n engl j med 370;23 june 5, 2014
to the fact that the brain, including the endocan-
nabinoid system, undergoes active development
during adolescence.6 Indeed, early and regular
marijuana use predicts an increased risk of mar-
ijuana addiction, which in turn predicts an in-
creased risk of the use of other illicit drugs.7 As
compared with persons who begin to use mari-
juana in adulthood, those who begin in adoles-
cence are approximately 2 to 4 times as likely to
have symptoms of cannabis dependence within
2 years after first use.8
Effect on Brain Development
The brain remains in a state of active, experi-
ence-guided development from the prenatal pe-
riod through childhood and adolescence until
the age of approximately 21 years.9 During these
developmental periods, it is intrinsically more
vulnerable than a mature brain to the adverse
long-term effects of environmental insults, such
as exposure to tetrahydrocannabinol, or THC,
the primary active ingredient in marijuana. This
view has received considerable support from
studies in animals, which have shown, for ex-
ample, that prenatal or adolescent exposure to
THC can recalibrate the sensitivity of the reward
system to other drugs10 and that prenatal expo-
sure interferes with cytoskeletal dynamics, which
are critical for the establishment of axonal con-
nections between neurons.11
As compared with unexposed controls, adults
who smoked marijuana regularly during adoles-
cence have impaired neural connectivity (fewer
fibers) in specific brain regions. These include
the precuneus, a key node that is involved in
functions that require a high degree of integra-
tion (e.g., alertness and self-conscious awareness),
and the fimbria, an area of the hippocampus
that is important in learning and memory.
Reduced functional connectivity has also been
reported in the prefrontal networks responsible
for executive function (including inhibitory con-
trol) and the subcortical networks, which pro-
cess habits and routines.
In addition, imaging
studies in persons who use cannabis have revealed
decreased activity in prefrontal regions and re-
duced volumes in the hippocampus.
Thus, cer-
tain brain regions may be more vulnerable than
others to the long-term effects of marijuana.
One study showed that selective down-regula-
tion of cannabinoid-1 (CB1) receptors in several
cortical brain regions in long-term marijuana
smokers was correlated with years of cannabis
smoking and was reversible after 4 weeks of
Changes in CB1 receptors were not
seen in subcortical regions.
The negative effect of marijuana use on the
functional connectivity of the brain is particu-
larly prominent if use starts in adolescence or
young adulthood,
which may help to explain
the finding of an association between frequent
use of marijuana from adolescence into adult-
hood and significant declines in IQ.
The im-
pairments in brain connectivity associated with
exposure to marijuana in adolescence are consis-
tent with preclinical findings indicating that the
cannabinoid system plays a prominent role in
synapse formation during brain development.
Possible Role as Gateway Drug
Epidemiologic and preclinical data suggest that
the use of marijuana in adolescence could inf lu-
ence multiple addictive behaviors in adulthood.
In rodents exposed to cannabinoids during ado-
lescence, there is decreased reactivity of the do-
pamine neurons that modulate the brain’s re-
ward regions.18 The exposure of rodents to
Table 1. Adverse Effects of Short-Term Use and Long-Term or Heavy Use
of Marijuana.
Effects of short-term use
Impaired short-term memory, making it difficult to learn and to retain infor-
Impaired motor coordination, interfering with driving skills and increasing
the risk of injuries
Altered judgment, increasing the risk of sexual behaviors that facilitate the
transmission of sexually transmitted diseases
In high doses, paranoia and psychosis
Effects of long-term or heavy use
Addiction (in about 9% of users overall, 17% of those who begin use in ado-
lescence, and 25 to 50% of those who are daily users)*
Altered brain development*
Poor educational outcome, with increased likelihood of dropping out of school*
Cognitive impairment, with lower IQ among those who were frequent users
during adolescence*
Diminished life satisfaction and achievement (determined on the basis of
subjective and objective measures as compared with such ratings in the
general population)*
Symptoms of chronic bronchitis
Increased risk of chronic psychosis disorders (including schizophrenia) in
persons with a predisposition to such disorders
* The effect is strongly associated with initial marijuana use early in adolescence.
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Adverse Health Effects of Marijuana Use
n engl j med 370;23 june 5, 2014
cannabis in utero alters the developmental regu-
lation of the mesolimbic dopamine system of af-
fected offspring.19 If reduced dopamine reactivity
in the brain’s reward regions does follow early
exposure to marijuana, this effect could help to
explain the increased susceptibility to drug abuse
and addiction to several drugs later in life, which
has been reported in most epidemiologic stud-
ies.20 This theory is also consistent with animal
models showing that THC can prime the brain
for enhanced responses to other drugs.21 Al-
though these findings support the idea that mar-
ijuana is a gateway drug, other drugs, such as
alcohol and nicotine, can also be categorized as
gateway drugs, since they also prime the brain
for a heightened response to other drugs.22 How-
ever, an alternative explanation is that people
who are more susceptible to drug-taking behav-
ior are simply more likely to start with marijuana
because of its accessibility and that their subse-
quent social interactions with other drug users
would increase the probability that they would
try other drugs.
Relation to Mental Illness
Regular marijuana use is associated with an in-
creased risk of anxiety and depression,23 but cau-
sality has not been established. Marijuana is also
linked with psychoses (including those associat-
ed with schizophrenia), especially among people
with a preexisting genetic vulnerability,24 and
exacerbates the course of illness in patients with
schizophrenia. Heavier marijuana use, greater
drug potency, and exposure at a younger age can
all negatively affect the disease trajectory (e.g., by
advancing the time of a first psychotic episode by
2 to 6 years).25
However, it is inherently difficult to establish
causality in these types of studies because factors
other than marijuana use may be directly associ-
ated with the risk of mental illness. In addition,
other factors could predispose a person to both
marijuana use and mental illness. This makes it
difficult to confidently attribute the increased
risk of mental illness to marijuana use.
Effect on School Performance and Lifetime
In the 2013 Monitoring the Future survey of
high-school students,26 6.5% of students in grade
12 reported daily or near-daily marijuana use,
and this figure probably represents an underesti-
mate of use, since young people who have
dropped out of school may have particularly high
rates of frequent marijuana use.27 Since marijua-
na use impairs critical cognitive functions, both
during acute intoxication and for days after use,28
many students could be functioning at a cogni-
tive level that is below their natural capability for
considerable periods of time. Although acute ef-
fects may subside after THC is cleared from the
brain, it nonetheless poses serious risks to health
that can be expected to accumulate with long-
term or heavy use. The evidence suggests that
such use results in measurable and long-lasting
cognitive impairments,16 particularly among
those who started to use marijuana in early ado-
lescence. Moreover, failure to learn at school,
even for short or sporadic periods (a secondary
effect of acute intoxication), will interfere with
the subsequent capacity to achieve increasingly
challenging educational goals, a finding that
may also explain the association between regular
marijuana use and poor grades.29
The relationship between cannabis use by
young people and psychosocial harm is likely to
be multifaceted, which may explain the incon-
sistencies among studies. For example, some
studies suggest that long-term deficits may be
reversible and remain subtle rather than dis-
abling once a person abstains from use.
studies show that long-term, heavy use of mari-
juana results in impairments in memory and
attention that persist and worsen with increas-
ing years of regular use
and with the initiation
of use during adolescence.
As noted above,
early marijuana use is associated with impaired
school performance and an increased risk of
dropping out of school,
although reports of
shared environmental factors that inf luence the
risks of using cannabis at a young age and drop-
ping out of school
suggest that the relationship
may be more complex. Heavy marijuana use has
been linked to lower income, greater need for
socioeconomic assistance, unemployment, crim-
inal behavior, and lower satisfaction with life.
Risk of motor-vehicle Accidents
Both immediate exposure and long-term expo-
sure to marijuana impair driving ability; mari-
juana is the illicit drug most frequently reported
in connection with impaired driving and acci-
dents, including fatal accidents.35 There is a rela-
tionship between the blood THC concentration
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new england journal
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and performance in controlled driving-simula-
tion studies,36 which are a good predictor of real-
world driving ability. Recent marijuana smoking
and blood THC levels of 2 to 5 ng per milliliter
are associated with substantial driving impair-
ment.37 According to a meta-analysis, the overall
risk of involvement in an accident increases by a
factor of about 2 when a person drives soon after
using marijuana.37 In an accident culpability
analysis, persons testing positive for THC (typi-
cal minimum level of detection, 1 ng per milli-
liter), and particularly those with higher blood
levels, were 3 to 7 times as likely to be responsi-
ble for a motor-vehicle accident as persons who
had not used drugs or alcohol before driving.38
In comparison, the overall risk of a vehicular ac-
cident increases by a factor of almost 5 for drivers
with a blood alcohol level above 0.08%, the legal
limit in most countries, and increases by a factor
of 27 for persons younger than 21 years of age.39
Not surprisingly, the risk associated with the use
of alcohol in combination with marijuana ap-
pears to be greater than that associated with the
use of either drug alone.37
Risk of Cancer and Other Effects on Health
The effects of long-term marijuana smoking on
the risk of lung cancer are unclear. For example,
the use of marijuana for the equivalent of 30 or
more joint-years (with 1 joint-year of marijuana
use equal to 1 cigarette [joint] of marijuana
smoked per day for 1 year) was associated with
an increased incidence of lung cancer and several
cancers of the upper aerodigestive tract; however,
the association disappeared after adjustment for
potential confounders such as cigarette smok-
ing.40 Although the possibility of a positive asso-
ciation between marijuana smoking and cancer
cannot be ruled out,41 the evidence suggests that
the risk is lower with marijuana than with tobac-
co.40 However, the smoking of cigarettes that con-
tain both marijuana and tobacco products is a
potential confounding factor with a prevalence
that varies dramatically among countries.
Marijuana smoking is also associated with
inflammation of the large airways, increased
airway resistance, and lung hyperinflation, as-
sociations that are consistent with the fact that
regular marijuana smokers are more likely to
report symptoms of chronic bronchitis than are
; however, the long-term effect of
low levels of marijuana exposure does not ap-
pear to be significant.
The immunologic com-
petence of the respiratory system in marijuana
smokers may also be compromised, as indicated
by increased rates of respiratory infections and
Marijuana use has also been as-
sociated with vascular conditions that increase
the risks of myocardial infarction, stroke, and
transient ischemic attacks during marijuana in-
The actual mechanisms underlying
the effects of marijuana on the cardiovascular
and cerebrovascular systems are complex and
not fully understood. However, the direct effects
of cannabinoids on various target receptors (i.e.,
CB1 receptors in arterial blood vessels) and the
indirect effects on vasoactive compounds
help explain the detrimental effects of marijua-
na on vascular resistance and coronary microcir-
Limitations of the Evidence
and Gaps in Knowledge
Most of the long-term effects of marijuana use
that are summarized here have been observed
among heavy or long-term users, but multiple
(often hidden) confounding factors detract from
our ability to establish causality (including the
frequent use of marijuana in combination with
other drugs). These factors also complicate our
ability to assess the true effect of intrauterine
exposure to marijuana. Indeed, despite the use
of marijuana by pregnant women,48 and animal
models suggesting that cannabis exposure dur-
ing pregnancy may alter the normal processes
and trajectories of brain development,49 our un-
derstanding of the long-term effects of prenatal
exposure to marijuana in humans is very poor.
The THC content, or potency, of marijuana,
as detected in confiscated samples, has been
steadily increasing from about 3% in the 1980s
to 12% in 2012
(Fig. 1A). This increase in THC
content raises concerns that the consequences of
marijuana use may be worse now than in the
past and may account for the significant in-
creases in emergency department visits by per-
sons reporting marijuana use
(Fig. 1B) and the
increases in fatal motor-vehicle accidents.
increase in THC potency over time also raises
questions about the current relevance of the
findings in older studies on the effects of mari-
juana use, especially studies that assessed long-
term outcomes.
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Adverse Health Effects of Marijuana Use
n engl j med 370;23 june 5, 2014
There is also a need to improve our under-
standing of how to harness the potential medi-
cal benefits of the marijuana plant without ex-
posing people who are sick to its intrinsic risks.
The authoritative report by the Institute of
Medicine, Marijuana and Medicine,
the potential benefits of smoking marijuana in
stimulating appetite, particularly in patients
with the acquired immunodeficiency syndrome
(AIDS) and the related wasting syndrome, and in
combating chemotherapy-induced nausea and
vomiting, severe pain, and some forms of spas-
ticity. The report also indicates that there is
some evidence for the benefit of using marijuana
to decrease intraocular pressure in the treatment
of glaucoma. Nonetheless, the report stresses
the importance of focusing research efforts on
the therapeutic potential of synthetic or pharma-
ceutically pure cannabinoids.
Some physicians
continue to prescribe marijuana for medicinal
purposes despite limited evidence of a benefit
(see box). This practice raises particular con-
cerns with regard to long-term use by vulnerable
populations. For example, there is some evi-
dence to suggest that in patients with symptoms
of human immunodeficiency virus (HIV) infec-
tion or AIDS, marijuana use may actually exac-
erbate HIV-associated cognitive deficits.
THC in Marijuana Samples (%)
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
BDrug-Related Emergency Department Visits
APotency of THC
No. of Emergency Department
Visits (in thousands)
Marijuana Cocaine Heroin
In combination Alone
Figure 1. Increases over Time in the Potency of Tetrahydrocannabinol (THC) in Marijuana and the Number of Emer-
gency Department Visits Involving Marijuana, Cocaine, or Heroin.
Panel A shows the increasing potency of marijuana (i.e., the percentage of THC) in samples seized by the Drug En-
forcement Administration (DEA) between 1995 and 2012.
Panel B provides estimates of the number of emergency
department visits involving the use of selected illicit drugs (marijuana, cocaine, and heroin) either singly or in com-
bination with other drugs between 2004 and 2011.
Among these three drugs, only marijuana, used either in com-
bination with other drugs or alone, was associated with significant increases in the number of visits during this peri-
od (a 62% increase when used in combination with other drugs and a 100% increase when used alone, P<0.05 for
the two comparisons).
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larly, more research is needed to understand the
potential effects of marijuana use on age-related
cognitive decline in general and on memory
impairment in particular.
Research is needed on the ways in which
government policies on marijuana affect public
health outcomes. Our understanding of the ef-
fects of policy on market forces is quite limited
(e.g., the allure of new tax-revenue streams from
the legal sale of marijuana, pricing wars, youth-
targeted advertising, and the emergence of can-
nabis-based medicines approved by the Food and
Drug Administration), as is our understanding
of the interrelated variables of perceptions about
Clinical Conditions with Symptoms That May Be Relieved by Treatment with Marijuana or Other Cannabinoids.*
Early evidence of the benefits of marijuana in patients with glaucoma (a disease associated with increased pressure in
the eye) may be consistent with its ability to effect a transient decrease in intraocular pressure,
but other, stan-
dard treatments are currently more effective. THC, cannabinol, and nabilone (a synthetic cannabinoid similar to
THC), but not cannabidiol, were shown to lower intraocular pressure in rabbits.
More research is needed to es-
tablish whether molecules that modulate the endocannabinoid system may not only reduce intraocular pressure
but also provide a neuroprotective benefit in patients with glaucoma.
Treatment of the nausea and vomiting associated with chemotherapy was one of the first medical uses of THC and other
THC is an effective antiemetic agent in patients undergoing chemotherapy,
but patients often state
that marijuana is more effective in suppressing nausea. Other, unidentified compounds in marijuana may enhance
the effect of THC (as appears to be the case with THC and cannabidiol, which operate through different antiemetic
Paradoxically, increased vomiting (hyperemesis) has been reported with repeated marijuana use.
AIDS-associated anorexia and wasting syndrome
Reports have indicated that smoked or ingested cannabis improves appetite and leads to weight gain and improved mood
and quality of life among patients with AIDS.
However, there is no long-term or rigorous evidence of a sustained
effect of cannabis on AIDS-related morbidity and mortality, with an acceptable safety profile, that would justify its
incorporation into current clinical practice for patients who are receiving effective antiretroviral therapy.
Data from
the few studies that have explored the potential therapeutic value of cannabinoids for this patient population are
Chronic pain
Marijuana has been used to relieve pain for centuries. Studies have shown that cannabinoids acting through central
CB1 receptors, and possibly peripheral CB1 and CB2 receptors,
play important roles in modeling nociceptive re-
sponses in various models of pain. These findings are consistent with reports that marijuana may be effective in
ameliorating neuropathic pain,
even at very low levels of THC (1.29%).
Both marijuana and dronabinol, a
pharmaceutical formulation of THC, decrease pain, but dronabinol may lead to longer-lasting reductions in pain
sensitivity and lower ratings of rewarding effects.
Cannabinoids (e.g., THC and cannabidiol) have substantial antiinflammatory effects because of their ability to induce
apoptosis, inhibit cell proliferation, and suppress cytokine production.
Cannabidiol has attracted particular inter-
est as an antiinflammatory agent because of its lack of psychoactive effects.
Animal models have shown that can-
nabidiol is a promising candidate for the treatment of rheumatoid arthritis
and for inflammatory diseases of the
gastrointestinal tract (e.g., ulcerative colitis and Crohn’s disease).
Multiple sclerosis
Nabiximols (Sativex, GW Pharmaceuticals), an oromucosal spray that delivers a mix of THC and cannabidiol, appears
to be an effective treatment for neuropathic pain, disturbed sleep, and spasticity in patients with multiple sclerosis.
Sativex is available in the United Kingdom, Canada, and several other countries
and is currently being reviewed
in phase 3 trials in the United States in order to gain approval from the Food and Drug Administration.
In a recent small survey of parents who use marijuana with a high cannabidiol content to treat epileptic seizures in their
11% (2 families out of the 19 that met the inclusion criteria) reported complete freedom from seizures,
42% (8 families) reported a reduction of more than 80% in seizure frequency, and 32% (6 families) reported a re-
duction of 25 to 60% in seizure frequency. Although such reports are promising, insufficient safety and efficacy data
are available on the use of cannabis botanicals for the treatment of epilepsy.
However, there is increasing evidence
of the role of cannabidiol as an antiepileptic agent in animal models.
* AIDS denotes acquired immunodeficiency syndrome, CB1 cannabinoid-1 receptor, and CB2 cannabinoid-2 receptor,
HIV human immunodeficiency virus, and THC tetrahydrocannabinol.
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Adverse Health Effects of Marijuana Use
n engl j med 370;23 june 5, 2014
use, types of use, and outcomes. Historically,
there has been an inverse correlation between
marijuana use and the perception of its risks
among adolescents (Fig. 2A). Assuming that this
inverse relationship is causal, would greater per-
missiveness in culture and social policy lead to
an increase in the number of young people who
are exposed to cannabis on a regular basis?
Among students in grade 12, the reported preva-
lence of regular marijuana smoking has been
steadily increasing in recent years and may soon
intersect the trend line for regular tobacco
smoking (Fig. 2B). We also need information
about the effects of second-hand exposure to
cannabis smoke and cannabinoids. Second-hand
exposure is an important public health issue in
the context of tobacco smoking, but we do not
have a clear understanding of the effects of
second-hand exposure to marijuana smoking.
Studies in states (e.g., Colorado, California, and
Washington) and countries (e.g., Uruguay, Por-
tugal, and the Netherlands) where social and
legal policies are shifting may provide important
data for shaping future policies.
Marijuana use has been associated with substan-
tial adverse effects, some of which have been de-
termined with a high level of confidence (Table 2).
Marijuana, like other drugs of abuse, can result
in addiction. During intoxication, marijuana can
interfere with cognitive function (e.g., memory
and perception of time) and motor function (e.g.,
coordination), and these effects can have detri-
mental consequences (e.g., motor-vehicle acci-
dents). Repeated marijuana use during adoles-
cence may result in long-lasting changes in brain
function that can jeopardize educational, profes-
sional, and social achievements. However, the ef-
fects of a drug (legal or illegal) on individual
health are determined not only by its pharmaco-
logic properties but also by its availability and
social acceptability. In this respect, legal drugs
Grade 12 Students (%)
BReported Daily Use of Cigarettes or Marijuana
ACorrelation between Perceived Risk and Use
Past-yr use
of marijuana
Perceived risk
of marijuana
Grade 12 Students (%)
Daily cigarette use
in previous 30 days
Daily marijuana use
in previous 30 days
Table 2. Level of Confidence in the Evidence for Adverse Effects of Marijuana
on Health and Well-Being.
Effect Overall Level
of Confidence*
Addiction to marijuana and other substances High
Abnormal brain development Medium
Progression to use of other drugs Medium
Schizophrenia Medium
Depression or anxiety Medium
Diminished lifetime achievement High
Motor vehicle accidents High
Symptoms of chronic bronchitis High
Lung cancer Low
* The indicated overall level of confidence in the association between marijuana
use and the listed effects represents an attempt to rank the strength of the
current evidence, especially with regard to heavy or long-term use and use
that starts in adolescence.
Figure 2. Use of Marijuana in Relation to Perceived
Risk and Daily Use of Tobacco Cigarettes or Marijuana
among U.S. Students in Grade 12, 1975–2013.
Panel A shows the inverse correlation between the per-
ception of the risk associated with marijuana use and
actual use. Perceived risk corresponds to the percent-
age of teenagers who reported that the use of marijuana
is dangerous. Panel B shows the percentage of students
who reported daily use of tobacco cigarettes or mari-
juana in the previous 30 days.
Data for both graphs are
from Johnston et al.
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new england journal
n engl j med 370;23 june 5, 2014
(alcohol and tobacco) offer a sobering perspec-
tive, accounting for the greatest burden of dis-
ease associated with drugs77 not because they are
more dangerous than illegal drugs but because
their legal status allows for more widespread ex-
posure. As policy shifts toward legalization of
marijuana, it is reasonable and probably prudent
to hypothesize that its use will increase and that,
by extension, so will the number of persons for
whom there will be negative health consequences.
No potential conflict of interest relevant to this article was
Disclosure forms provided by the authors are available with
the full text of this article at
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... Researchers have hypothesized this association may be due to the drug's effects on the developing brain and neurocognitive functioning of adolescents (Volkow et al. 2014). On the other hand, research has also shown marijuana use in adolescence to not have a strong influence on adult mental health outcomes (Schaefer et al. 2021) including suicidal behavior (Borges et al. 2016), or the long-term mental health outcome to be attenuated when controlling for a rich set of environmental confounders (Copeland et al. 2022). ...
... Because most marijuana use is initiated during adolescence (Haas et al. 2018), identifying factors that underlie youth marijuana use is vital to developing effective prevention strategies. This is of policy importance given ongoing brain and psychosocial developments during adolescence (Volkow et al. 2014) and the impact it can have on long-term mental health outcomes. ...
Full-text available
We estimate the long-term effect of initiating marijuana use in adolescence on several mental health outcomes later in life. We use the first two waves (1994–1996) and the fifth wave (2016–2018) of the National Longitudinal Study of Adolescent to Adult Health (Add Health) and estimate instrumental variables models with school-level fixed effects, where the instrument is the respondents’ perceptions about their friends’ marijuana use. We find that marijuana use in adolescence is associated with a significant increase in anxiety approximately twenty years later. The increase in anxiety is only present among females and is stronger among females who used marijuana regularly as adolescents.
... Among secondary school students between 8th and 12th grade in Chile, the prevalence of alcohol use was 57% in the past year and 31% in the past month, of which 62% had taken five or more standard drinks (Servicio Nacional para la Prevención y Rehabilitación del Consumo de Drogas y Alcohol, 2018). Cannabis use is also frequent in adolescents and is associated with adverse outcomes (Silins et al., 2014;Volkow et al., 2014;Degenhardt et al., 2016;Hall and Lynskey, 2016). In recent years, the use of cannabis among secondary school students in Chile has increased. ...
... It increased from 14.8% in 2001 to 30.9% in 2017 (Servicio Nacional para la Prevención y Rehabilitación del Consumo de Drogas y Alcohol, 2018; Libuy et al., 2020), while the average one-year prevalence of adolescent cannabis use worldwide was 4.7% (United Nations Office on Drugs and Crime, 2020). Initiation of substance use at a young age increases the risk of developing substance use disorders and adverse long-term outcomes (Volkow et al., 2014;Jordan and Andersen, 2017;Levine et al., 2017;Spear, 2018). Among tenth-grade students in Chile, the age of onset of substance use is associated with suicide-related behaviors (Nuñez et al., 2022). ...
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Background Adolescent alcohol and cannabis use are common in Chile. The present study aimed to assess the relationship between perceived parenting practices and alcohol and cannabis use among adolescents in a Latin American context. Methods We adapted and implemented a substance use prevention strategy in Chile, which included surveys of tenth-grade students from six municipalities in the Metropolitan Region of Greater Santiago. We assessed the reliability and factorial structure of the parenting scale with 16 items, which formed part of the survey. We dichotomized parenting scores into high (above the median) and low. The association of parenting practices with alcohol and cannabis use in adolescents was assessed using multivariate multilevel regression models. Results A total of 7,538 tenth-grade students from 118 schools were included in the study. The 16-item scale of parenting practices showed good internal consistency (Omega total = 0.84), and three factors representing Relationship between parents and adolescents , Norms and monitoring , and Parents knowing their children’s friends and the parents of their children’s friends . High total scores of parenting were associated with lower odds of lifetime alcohol use (OR 0.57; 95% CI: 0.49–0.65), past-month alcohol use (OR 0.63; 95% CI: 0.57–0.70), lifetime drunkenness (OR 0.64; 95% CI: 0.58–0.72), and lifetime cannabis use (OR 0.54; 95% CI: 0.47–0.61). Above median scores on each parenting subscale were associated with significantly lower odds of substance use. The strongest associations were observed for the subscale Norms and monitoring . Interactions between parenting and gender showed a significantly stronger effect of parenting practices on alcohol and cannabis use among girls. Conclusion Different types of parenting practices were associated with a lower prevalence of adolescent alcohol and cannabis use. Improving parenting practices has the potential to prevent adolescent substance use in Chile, especially among girls.
... Risks to the pregnant or lactating person are similar to the general risks of cannabis consumption, and include respiratory and cardiovascular disorders, 20,21 cannabis hyperemesis syndrome, 22 and mental health and substance use disorders. 20,[23][24][25] Cannabis use during pregnancy may also be associated with an elevated risk of anemia. 26 Clinical evidence about the risks to the fetus or infant associated with perinatal cannabis use is still emerging. ...
Full-text available
Background Multiple studies have demonstrated that pregnant and lactating people who use cannabis perceive a variety of benefits from that use, offering some explanation of why rates of use continue to increase. Objectives The aim of this study was to explore pregnant and lactating people’s perceptions of the risks of cannabis use and understand what steps, if any, they take to mitigate these risks. Design Qualitative description. Methods We analyzed semi-structured interviews with 52 Canadians who made the decision to start, stop, or continue using cannabis during pregnancy or lactation between 2019 and 2021. Data collection iterated with analysis. We used a conventional (inductive) approach to content analysis. Results Perception of risk was found to be an essential component of decision-making about cannabis use. We identified a cycle of “risk identification,” “management,” and “observation” of effects. First, the pregnant or lactating person assesses the risks and weighs them against the perceived benefits of cannabis use. Second, they take action to minimize risks, with some choosing abstinence. Others, often those who were using cannabis to manage symptoms, continued cannabis use but devised a variety of other risk mitigation strategies such as, decreasing the amount or frequency of their use, changing the form of cannabis, and strategically timing their use with caregiving responsibilities. The final stage of the cycle involves seeking information about whether or not the initial perceived risk has manifested after implementing mitigation strategies, through observations and clinical information about the pregnancy or child. Conclusion Participants consistently engaged in deliberation about the risks and benefits associated with their perinatal cannabis use. Nearly all implemented strategies intended to minimize risk. Our results highlight the need for more research to inform clear public health messaging about risk mitigation to minimize the potential harms of perinatal cannabis use. This work informs clinicians about patient-perceived risks and mitigation strategies which could in turn help inform shared decision-making conversations.
... Cannabis use is two to three times higher among individuals with anxiety or depression compared with those without these conditions [22][23][24]. Also, cannabis use is a risk factor for the development of poor mental health and regular use may worsen depressive symptoms [25,26]. Previous studies have shown that mental health disorders are associated with heavy use and dependence of nicotine and cannabis as well as a decreased likelihood of successful cessation [27,28]. ...
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Background Little is known about whether people who use both tobacco and cannabis (co-use) are more or less likely to have mental health disorders than single substance users or non-users. We aimed to examine associations between use of tobacco and/or cannabis with anxiety and depression. Methods We analyzed data from the COVID-19 Citizen Science Study, a digital cohort study, collected via online surveys during 2020–2022 from a convenience sample of 53,843 US adults (≥ 18 years old) nationwide. Past 30-day use of tobacco and cannabis was self-reported at baseline and categorized into four exclusive patterns: tobacco-only use, cannabis-only use, co-use of both substances, and non-use. Anxiety and depression were repeatedly measured in monthly surveys. To account for multiple assessments of mental health outcomes within a participant, we used Generalized Estimating Equations to examine associations between the patterns of tobacco and cannabis use with each outcome. Results In the total sample (mean age 51.0 years old, 67.9% female), 4.9% reported tobacco-only use, 6.9% cannabis-only use, 1.6% co-use, and 86.6% non-use. Proportions of reporting anxiety and depression were highest for the co-use group (26.5% and 28.3%, respectively) and lowest for the non-use group (10.6% and 11.2%, respectively). Compared to non-use, the adjusted odds of mental health disorders were highest for co-use ( Anxiety : OR = 1 . 89 , 95%CI = 1 . 64–2 . 18; Depression : OR = 1 . 77 , 95%CI = 1 . 46–2 . 16 ), followed by cannabis-only use, and tobacco-only use. Compared to tobacco-only use, co-use (OR = 1 . 35 , 95%CI = 1 . 08–1 . 69) and cannabis-only use (OR = 1 . 17 , 95%CI = 1 . 00–1 . 37 ) were associated with higher adjusted odds for anxiety, but not for depression. Daily use (vs. non-daily use) of cigarettes, e-cigarettes, and cannabis were associated with higher adjusted odds for anxiety and depression. Conclusions Use of tobacco and/or cannabis, particularly co-use of both substances, were associated with poor mental health. Integrating mental health support with tobacco and cannabis cessation may address this co-morbidity.
... 2019), respiratory symptoms (Ghasemiesfe et al., 2018), lower educational attainment (among youth) (Lynskey & Hall. 2000), downward socialclass mobility, financial difficulties, work problems, and relationship problems , risky behaviors (motor vehicle crashes) (Hall, 2015;Li et al., 2012), mental health conditions and marijuana use disorders ; National Academies of Sciences Engineering and Medicine 2017; Volkow et al., 2014). As of today, there is no medication approved by the U.S. Food and Drug Administration (FDA) for the treatment of marijuana use disorder (addiction) (National Institute on Drug Abuse, 2020). ...
Full-text available
In 2019, Marijuana Use Disorder (MUD) (DSM-IV) affected approximately 4.8 million (1.8%) Americans aged 12 and older. Given the continued evolving state-level marijuana/cannabis legislation, increased patterns of use in the general population, and nuances of diagnostic criteria (from DSM-IV to DSM-5) in a U.S. national survey, the objective of this study is to estimate and characterize individuals who met the DSM-5 diagnostic criteria for MUD in the past year. Using public-use files from the 2020 National Survey on Drug Use and Health (NSDUH), we examined sociodemographic and selected behavioral indicators associated with MUD. NSDUH participants (32,893 individuals) were weighted to the U.S. noninstitutionalized civilian population. The analytic sample included 2,151 unweighted individual respondents aged 12 years and older who met the DSM-5 diagnostic criteria of MUD in the past year. We excluded 299 respondents from the analyses. Descriptive and logistic regression were applied. In 2020, approximately 13.9 million Americans aged 12 and older (5.0%) met the diagnostic criteria (DSM-5) of MUD, with 9.5 million individuals (3.4%) categorized as having MUD mild disorders (2–3 DSM-5 criteria). Our data showed differences in the percentage of MUD by sociodemographic (age, sex, race/ethnicity, household income, employment status, education level, health insurance, and health status) and selected behavioral health indicators (addiction, social environment, market/acquisition, treatment, substance use, and mental health-related questions). Logistic regression findings depict relevant comorbidities related to behavioral health (substance use and mental health). These results represent the most updated U.S. national baseline for MUD estimates. Our findings also confirm that the co-occurrence of substance use, and selected mental health conditions are common, prevalent, and correlated among individuals with MUD. Continued monitoring of MUD and other related behavioral indicators remains important, especially among youth and vulnerable ethnic groups.
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The rising prevalence and legalization of cannabis worldwide have underscored the need for a comprehensive understanding of its biological impact, particularly on mental health. Epigenetic mechanisms, specifically DNA methylation, have gained increasing recognition as vital factors in the interplay between risk factors and mental health. This study aimed to explore the effects of current cannabis use and potency on DNA methylation in two independent cohorts of individuals experiencing first-episode psychosis (FEP) compared to control subjects. The combined sample consisted of 682 participants (cannabis users (n = 188) and never users (n = 494)). DNA methylation profiles were generated on blood-derived DNA samples using the Illumina DNA methylation array platform. Each cohort was analysed individually and then meta-analysed. We identified one CpG site (cg11669285) in the CAVIN1 gene that showed differential methylation with current cannabis use, surpassing the array-wide significance threshold, and independent of the tobacco-related epigenetic signature. Furthermore, a CpG site localized in the MCU gene (cg11669285) achieved array-wide significance in the analysis of high-potency cannabis use. Pathway and regional analyses identified cannabis-related epigenetic deviations in genes linked to immune and mitochondrial function, both of which are known to be influenced by cannabinoids. Notably, the analyses focused on first-onset psychoses identified differential methylation at nominal significance in a CpG site situated in the TRPV2 gene, which is known to be activated by cannabinoids. Overall, these findings contribute to our understanding of the epigenetic consequences of current cannabis use in the general population and in first-episode psychosis and highlight potential molecular pathways affected by cannabis exposure.
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In recent years, there have been important changes related to marijuana use at the therapeutic, legislative, and social levels. Our goal is to know how they have influenced scientific research through the articles published in the Health Sciences journals in the last two decades (2001–2020). Marijuana articles included in the Web of Science Core Collection were retrieved, including their PubMed identifier (PMID) which was used to check whether these articles were also indexed in PubMed, obtaining a total of 36,982 documents. After, their descriptive terms (MeSH) on the specific branches of Chemicals and Drugs, Psychiatry and Psychology, and Anthropology, Education, Sociology, and Social Phenomena were extracted to (1) conduct a correspondence analysis between terms and years to know the temporary evolution and (2) study the frequency per years of the terms “marijuana abuse,” “marijuana use,” and “medical marijuana.” The temporary analysis of the three branches showed a change in the use of terms from those more punitive to others more generic, more related to therapeutic issues, or more normalizing. The analysis of frequency showed that the most recent terms “marijuana use” and “medical marijuana” have gained weight on “marijuana abuse.” Starting with research on the negative consequences and ending with elements related to legislation and the therapeutic possibilities of marijuana shows a trend that has not been observed for any other drug. It would be advisable for scientific research and policy actions to take this into account in the development of prevention programs.
Context: Many clinicians, trainers, and athletes do not have a true understanding of the effects of commonly used performance-enhancing drugs (PEDs) on performance and health. Objective: To provide an evidence-based review of 7 commonly used pharmacological interventions for performance enhancement in athletes. Data sources: PubMed and Scopus databases were searched on April 8, 2022. Study selection: Systematic reviews (SRs) and meta-analyses (MAs) assessing the performance-enhancing effects of the following interventions were included: androgenic anabolic steroids (AAS), growth hormone (GH), selective androgen receptor modulators (SARMs), creatine, angiotensin-converting enzyme (ACE)-inhibitors, recombinant human erythropoietin (rHuEPO), and cannabis. Study design: Umbrella review of SRs and MAs. Level of evidence: Level 4. Data extraction: Primary outcomes collected were (1) body mass, (2) muscle strength, (3) performance, and (4) recovery. Adverse effects were also noted. Results: A total of 27 papers evaluating 5 pharmacological interventions met inclusion criteria. No studies evaluating SARMs or ACE-inhibitors were included. AAS lead to a 5% to 52% increase in strength and a 0.62 standard mean difference in lean body mass with subsequent lipid derangements. GH alters body composition, without providing a strength or performance benefit, but potential risks include soft tissue edema, fatigue, arthralgias, and carpel tunnel syndrome. Creatine use during resistance training can safely increase total and lean body mass, strength, and performance in high-intensity, short-duration, repetitive tasks. Limited evidence supports rHuEPO benefit on performance despite increases in both VO2max and maximal power output, and severe cardiovascular risks are documented. Cannabis provides no performance benefit and may even impair athletic performance. Conclusion: In young healthy persons and athletes, creatine can safely provide a performance-enhancing benefit when taken in controlled doses. AAS, GH, and rHuEPO are associated with severe adverse events and do not support a performance benefit, despite showing the ability to change bodily composition, strength, and/or physiologic measures. Cannabis may have an ergolytic, instead of ergogenic, effect.
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Drugged driving is a safety issue of increasing public concern. Using data from the Fatality Analysis Reporting System for 1999-2010, we assessed trends in alcohol and other drugs detected in drivers who were killed within 1 hour of a motor vehicle crash in 6 US states (California, Hawaii, Illinois, New Hampshire, Rhode Island, and West Virginia) that routinely performed toxicological testing on drivers involved in such crashes. Of the 23,591 drivers studied, 39.7% tested positive for alcohol and 24.8% for other drugs. During the study period, the prevalence of positive results for nonalcohol drugs rose from 16.6% in 1999 to 28.3% in 2010 (Z = -10.19, P < 0.0001), whereas the prevalence of positive results for alcohol remained stable. The most commonly detected nonalcohol drug was cannabinol, the prevalence of which increased from 4.2% in 1999 to 12.2% in 2010 (Z = -13.63, P < 0.0001). The increase in the prevalence of nonalcohol drugs was observed in all age groups and both sexes. These results indicate that nonalcohol drugs, particularly marijuana, are increasingly detected in fatally injured drivers.
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Unlabelled: Cannabis use is associated with an earlier age of onset of psychosis (AOP). However, the reasons for this remain debated. Methods: We applied a Cox proportional hazards model to 410 first-episode psychosis patients to investigate the association between gender, patterns of cannabis use, and AOP. Results: Patients with a history of cannabis use presented with their first episode of psychosis at a younger age (mean years = 28.2, SD = 8.0; median years = 27.1) than those who never used cannabis (mean years = 31.4, SD = 9.9; median years = 30.0; hazard ratio [HR] = 1.42; 95% CI: 1.16-1.74; P < .001). This association remained significant after controlling for gender (HR = 1.39; 95% CI: 1.11-1.68; P < .001). Those who had started cannabis at age 15 or younger had an earlier onset of psychosis (mean years = 27.0, SD = 6.2; median years = 26.9) than those who had started after 15 years (mean years = 29.1, SD = 8.5; median years = 27.8; HR = 1.40; 95% CI: 1.06-1.84; P = .050). Importantly, subjects who had been using high-potency cannabis (skunk-type) every day had the earliest onset (mean years = 25.2, SD = 6.3; median years = 24.6) compared to never users among all the groups tested (HR = 1.99; 95% CI: 1.50- 2.65; P < .0001); these daily users of high-potency cannabis had an onset an average of 6 years earlier than that of non-cannabis users. Conclusions: Daily use, especially of high-potency cannabis, drives the earlier onset of psychosis in cannabis users.
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.
Children exposed in utero to cannabis present permanent neurobehavioral and cognitive impairments. Psychoactive constituents from Cannabis spp., particularly Δ(9)-tetrahydrocannabinol (THC), bind to cannabinoid receptors in the fetal brain. However, it is unknown whether THC can trigger a cannabinoid receptor-driven molecular cascade to disrupt neuronal specification. Here, we show that repeated THC exposure disrupts endocannabinoid signaling, particularly the temporal dynamics of CB1 cannabinoid receptor, to rewire the fetal cortical circuitry. By interrogating the THC-sensitive neuronal proteome we identify Superior Cervical Ganglion 10 (SCG10)/stathmin-2, a microtubule-binding protein in axons, as a substrate of altered neuronal connectivity. We find SCG10 mRNA and protein reduced in the hippocampus of midgestational human cannabis-exposed fetuses, defining SCG10 as the first cannabis-driven molecular effector in the developing cerebrum. CB1 cannabinoid receptor activation recruits c-Jun N-terminal kinases to phosphorylate SCG10, promoting its rapid degradation in situ in motile axons and microtubule stabilization. Thus, THC enables ectopic formation of filopodia and alters axon morphology. These data highlight the maintenance of cytoskeletal dynamics as a molecular target for cannabis, whose imbalance can limit the computational power of neuronal circuitries in affected offspring.
Marijuana has been used to relieve pain for centuries, but its analgesic mechanism has only been understood during the past two decades. It is mainly mediated by its constituents, cannabinoids, through activating central cannabinoid 1 (CB1) receptors, as well as peripheral CB1 and CB2 receptors. CB2-selective agonists have the benefit of lacking CB1 receptor-mediated CNS side effects. Anandamide and 2-arachidonoylglycerol (2-AG) are two intensively studied endogenous lipid ligands of cannabinoid receptors, termed endocannabinoids, which are synthesized on demand and rapidly degraded. Thus, inhibitors of their degradation enzymes, fatty acid amide hydrolase and monoacylglycerol lipase (MAGL), respectively, may be superior to direct cannabinoid receptor ligands as a promising strategy for pain relief. In addition to the antinociceptive properties of exogenous cannabinoids and endocannabinoids, involving their biosynthesis and degradation processes, we also review recent studies that revealed a novel analgesic mechanism, involving 2-AG in the periaqueductal gray (PAG), a midbrain region for initiating descending pain inhibition. It is initiated by Gq-protein-coupled receptor (GqPCR) activation of the phospholipase C (PLC)-diacylglycerol lipase (DAGL) enzymatic cascade, generating 2-AG that produces inhibition of GABAergic transmission (disinhibition) in the PAG, thereby leading to analgesia. This GqPCR-PLC-DAGL-2-AG retrograde disinhibition mechanism in the PAG can be initiated by activating type 5 metabotropic glutamate receptor (mGluR5), muscarinic acetylcholine (M1/M3), and orexin (OX1) receptors. mGluR5-mediated disinhibition can be initiated by glutamate transporter inhibitors, or indirectly by substance P, neurotensin, cholecystokinin, capsaicin, and AM404, the bioactive metabolite of acetaminophen in the brain. The putative role of 2-AG generated after activating the above neurotransmitter receptors in stress-induced analgesia is also discussed.
Unlabelled: Application of cannabinoids and endocannabinoids to perfused vascular beds or individual isolated arteries results in changes in vascular resistance. In most cases, the result is vasorelaxation, although vasoconstrictor responses are also observed. Cannabinoids also modulate the actions of vasoactive compounds including acetylcholine, methoxamine, angiotensin II and U46619 (thromboxane mimetic). Numerous mechanisms of action have been proposed including receptor activation, potassium channel activation, calcium channel inhibition and the production of vasoactive mediators such as calcitonin gene-related peptide, prostanoids, NO, endothelial-derived hyperpolarizing factor and hydrogen peroxide. The purpose of this review is to examine the evidence for the range of receptors now known to be activated by cannabinoids. Direct activation by cannabinoids of CB1 , CBe , TRPV1 (and potentially other TRP channels) and PPARs in the vasculature has been observed. A potential role for CB2, GPR55 and 5-HT1 A has also been identified in some studies. Indirectly, activation of prostanoid receptors (TP, IP, EP1 and EP4 ) and the CGRP receptor is involved in the vascular responses to cannabinoids. The majority of this evidence has been obtained through animal research, but recent work has confirmed some of these targets in human arteries. Vascular responses to cannabinoids are enhanced in hypertension and cirrhosis, but are reduced in obesity and diabetes, both due to changes in the target sites of action. Much further work is required to establish the extent of vascular actions of cannabinoids and the application of this research in physiological and pathophysiological situations. Linked articles: This article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit