marihuana

Clinical Toxicology (2009) 47, 517-524
Copyright (c) Informa UK, Ltd.
ISSN: 1556-3650 print / 1556-9519 online
DOI: 10.1080/15563650903074507
LCLT
REVIEW
Chronic toxicology of cannabis
Cannabis toxicology
ALBERT STUART REECE
Medical School, University of Queensland, Highgate Hill, Brisbane, QLD, Australia
Introduction. Cannabis is the most widely used illicit drug worldwide. As societies reconsider the legal status of cannabis, policy makers
and clinicians require sound knowledge of the acute and chronic effects of cannabis. This review focuses on the latter.
Methods. A
systematic review of Medline, PubMed, PsychInfo, and Google Scholar using the search terms "cannabis," "marijuana," "marihuana,"
"toxicity," "complications," and "mechanisms" identified 5,198 papers. This list was screened by hand, and papers describing mechanisms
and those published in more recent years were chosen preferentially for inclusion in this review. Findings. There is evidence of psychiatric,
respiratory, cardiovascular, and bone toxicity associated with chronic cannabis use. Cannabis has now been implicated in the etiology of
many major long-term psychiatric conditions including depression, anxiety, psychosis, bipolar disorder, and an amotivational state.
Respiratory conditions linked with cannabis include reduced lung density, lung cysts, and chronic bronchitis. Cannabis has been linked in a
dose-dependent manner with elevated rates of myocardial infarction and cardiac arrythmias. It is known to affect bone metabolism and also
has teratogenic effects on the developing brain following perinatal exposure. Cannabis has been linked to cancers at eight sites, including
children after in utero maternal exposure, and multiple molecular pathways to oncogenesis exist. Conclusion. Chronic cannabis use is
associated with psychiatric, respiratory, cardiovascular, and bone effects. It also has oncogenic, teratogenic, and mutagenic effects all of
which depend upon dose and duration of use.
Keywords
Cannabis; Psychopathology; Respiratory pathology; Psychosis; Depression; Chronic bronchitis; Chronic asthma;
Genotoxicity; Oncogenesis; Toxicity; Toxicology
For personal use only.
Introduction
mechanisms and those published in more recent years were
chosen preferentially. Review papers are cited where appro-
According to the United Nations Office of Drugs and Crime,
priate to introduce a large or detailed field for the interested
there are some 165 million users of cannabis worldwide,
reader. Few case reports are included and they are specifi-
making it the most widely used illicit drug.1 This review
cally flagged where they occur; those that are cited have been
examines the psychiatric, respiratory, cardiovascular, and
included largely because they suggest important pathophysio-
bone effects associated with chronic cannabis use and the
logical mechanisms.
neurodevelopmental, genotoxic, mutagenic, and oncogenic
effects of cannabis.
Psychiatric and social disorders
Clinical Toxicology Downloaded from www.informahealthcare.com by HINARI on 09/11/09
Methodology
An authoritative meta-analysis of cannabis-related psychopa-
thology has been published,2 with an accompanying edito-
A systematic review of Medline, PubMed, PsychInfo, Google
rial.3 Another review found an elevated risk of psychosis in
Scholar, Scopus, Proquest, Web of Knowledge, and Ebsco-
many studies, with an odds ratio (OR) of about 2.3.4 A simi-
Host using the search terms "cannabis," "marijuana," or
lar meta-analysis from the Netherlands found a pooled OR
"marihuana" identified 14,065 papers, excluding duplicates.
for psychosis of 2.1.5 Several studies from diverse cultures
When the search terms "toxicity," "complications," and
have confirmed the elevated risk of psychosis and schizo-
"mechanisms" were added, the list narrowed to 5,198 papers.
phreniform spectrum disorders5-17 following high levels of
This list was screened by hand, and original papers describing
cannabis use, particularly when cannabis consumption has
commenced at a young age.14,18 Cannabis use has been found
to exacerbate pre-existing psychotic disorders.5,15
Received 27 April 2009; accepted 28 May 2009.
There is a similar and increasing literature around both
Address correspondence to Albert Stuart Reece, Medical School,
bipolar disorder19-21 and depression.22-25 Although the psy-
University of Queensland, 39 Gladstone Road, Highgate Hill,
choneurological effects of cannabis are usually stereotypi-
Brisbane, QLD 4101, Australia. E-mail: sreece@bigpond.net.au;
cally characterized as a depressant, both its use and the
asreece@bigpond.net.au.

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Clinical Toxicology vol. 47 no. 6 2009
518
A.S. Reece
withdrawal state are accompanied frequently by psychomotor
large airway inflammation and obstruction and hyperinflation
agitation, which has been implicated causally with interper-
but was seldom associated with macroscopic emphysema,
sonal violence.26 Interestingly, in a series of forensic exami-
with a dose equivalence of one cannabis joint to 2.5-5 ciga-
nations of suicide, cannabis use was associated with the most
rettes. These findings were supported by an accompanying
violent means of death, particularly severe motor vehicle
editorial39 and press release.40 Decreased lung density has
accidents.27
also been noted with increased lung volumes, signs of
In 1972 Nahas28 drew attention to the devastating effects
destruction of lung tissue, cyst formation, and emphysema-
of cannabis in Egypt as quantified by carefully prepared and
tous change with secondary pneumothorax because of
formally psychologically documented surveys from that
bullous rupture.41-43
country. Higher levels of anxiety, impaired memory, poor
Cannabis smoke is known to contain several potent carcin-
concentration, impaired learning ability, and psychomotor
ogens including anthrocyclines, nitrosamines, polycyclic aro-
impairment including reduced quality and quantity of work
matic hydrocarbons, terpenes, and vinyl chloride.4,35,44-47 As
were seen in these users. In addition, a common dependency
a consequence, cannabis use is associated with cancer of the
syndrome was observed, which made exit from the dependent
lung.30-32
state both difficult and rare.28 Geographical microclustering
of cannabis use has been demonstrated, which has the effect
of establishing local socially normative use patterns.29 Both
Cardiovascular effects
in northern Africa and in New Zealand communities exist
where cannabis use is common, and intellectual impairment,
Cannabis exposure is known to cause phasic systemic vasodi-
psychomotor slowing, poor work capacity, and severe social
lation, mild hypertension, and tachycardia often associated
deprivation are entrenched.30-32
with postural hypotension, and a reduced duration and
Lee and colleagues33,34 have published several descriptions
increased heart rate response to exercise.48-51 Some but not
of heavy, problematic, and refractory cannabis use in remote
all these effects are mediated by the autonomic nervous sys-
indigenous communities of the Northern Territory and across
tem. Tolerance to many of these acute effects with time
northern Australia more generally. A substantial proportion
appears. In most young healthy patients such changes are
(31-62%) of users' median weekly income and up to 10% of
clearly generally well tolerated,48,50 but this is not universally
the total community income were spent on cannabis. Ninety
true and several exceptions cited below are of considerable
percent smoked cannabis heavily (more than six cones daily)
pathophysiological interest. Such generic reassurances
and were not able to cease use. Severe mental illness was
cannot be provided to patients with pre-existing coronary or
For personal use only.
commonplace, as were depression, suicidal ideation, auditory
atherosclerotic disease.50,52
hallucinations, and imprisonment. There was less participa-
Several case reports associate cannabis use with infarctions
tion in employment, education, or training. Community
of kidney,53 brain,54-60 heart61-65, and digits,66,67 and of pri-
violence escalated when cannabis supplies from distant cen-
apism in humans with sickle cell disease.68 An association
ters were interrupted. Most users had not "matured out" of
between cannabis use and pedal gangrene has also been
dependent cannabis use even 5 years later. It is particularly
described in a 27-year old.67 Some 50 cases of cannabis
noteworthy that these same communities had largely success-
arteritis have been reported in the literature.67 Cannabis use
fully defeated alcohol abuse, primarily by tight restrictive
can acutely trigger myocardial infarction,69 which has also
policies aimed at severely curtailing alcohol supply. The
been documented in a 25-year-old man with no other cardiac
authors concluded that cannabis was both an important cause
risk factors and normal coronary arteries at angiography.62
Clinical Toxicology Downloaded from www.informahealthcare.com by HINARI on 09/11/09
and a consequence of ongoing severe social disadvantage and
Coronary no-flow phenomenon has been observed after acute
deprivation.
cannabis use.57 Cardiomyopathy has also been reported in a
young man.70 One large study of 1,913 adults conducted in
the United States found both a significant association
Respiratory effects
between myocardial infarction and cannabis use, and a dose-
response effect, with adjusted hazard ratios of 2.5 and 4.2 for
Both the Thoracic Society of Australia and New Zealand35
less than weekly and weekly use, respectively.52
and the British Lung Foundation4 have issued major state-
Reversible cerebral vasospasm71 as well as slowing and
ments in recent years acknowledging the known deleterious
flow reversal in the middle cerebral artery72 has also been
effects of cannabis on the lungs. Cannabis is smoked
documented and attributed to cannabis use. On the contrary,
differently from tobacco. Users commonly inhale deeply to a
the same authors also reported an increase of blood flow in
maximal breath and then retain the smoke in the lungs, which
the cerebral frontal lobes.73 Several case reports have
generates higher pressures during breath holding and on
described a cannabis-associated inflammatory angiitis,61,74,75
expiration.35-37
which can be so severe as to mimic Buerger's disease (throm-
Cannabis smoke stimulates inflammation in the airways so
boangiitis obliterans or "disappearing artery syndrome").
that its long-term use is associated with the development of
In a study in 19 patients, alterations of the cardiac pressure
chronic bronchitis. A New Zealand study38 demonstrated
cycle were found with a highly significant prolongation of

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Clinical Toxicology vol. 47 no. 6 2009
Cannabis toxicology
519
both electromechanical systole (by 17 ms) and left ventricular
cannabis-exposed babies.108 Many of these defects were
ejection time, in the context of a reduced pre-ejection period
major and involved the brain (encephalocoele, hydrocephaly,
(systolic pressure upstroke), a tachycardia of 132 bpm, and
microcephaly, anophthalmia/microphthalmia), cardiovascula-
unchanged brachial systemic pressures.76 These more abrupt
ture (tetralogy of Fallot, ventricular septal defect, atrial septal
cardiac pressure changes imply increased cardiac work in the
defect, and right and left heart atretic syndromes), gas-
context of a prolonged QTc interval and reduced opportunity
trointestinal system (pyloric stenosis, intestinal atresias and
for myocardial perfusion (the "Buckberg index"), which is
stenoses, and gastroschisis), and limbs (polydatyly, syndac-
limited to the diastolic phase of the cardiac cycle.77,78 Hence,
tyly, and reduction deformities of the upper and lower limbs);
this scenario combines both an adverse mechanical and elec-
oro-facial clefts were also reported. One large American
trical profile in the context of reduced coronary perfusion and
study found a somewhat elevated risk of anencephaly (OR =
an altered endothelial, coagulation, angiogenic,79 and inflam-
1.7, CI = 0.9-3.4).109 The association with gastroschisis has
matory milieu.
been confirmed by other investigators.110
Cannabis has also been linked with elevated rates of car-
The dominant theme to emerge from studies of perinatal
diac arrhythmias in several case reports.80 Generally, these
exposure is that of impaired executive cortical functioning
are supraventricular and trivial,81-83 but well-documented
reflected in reduced attention and analytical behavior and
cases of lethal ventricular arrythmias do exist57 and one such
visuospatial analysis and hypothesis testing;111 parent-rated
was recently reported from a man who survived and whose
behavioral problems, language comprehension, and
episode was recorded on his implantable defibrillator.84
distractibility112; and inattention, hyperactivity, impulsivity,
Elevated plasma concentrations of the endocannabinoid
and substance use disorders.113 Indeed, close agreement
2-arachidonylglycerol status have been associated in an
between human and animal studies of perinatal exposure has
Italian study of 62 patients with an exacerbation of the car-
been shown.113 Such changes emerge from as early as the
diovascular risk profile with worse concentrations of total
first weeks of life and persist in children in longitudinal stud-
cholesterol, high-density lipoprotein cholesterol, body mass
ies into the school ages. Importantly, cannabis seemed to
index, intra-abdominal obesity, and adiponectin.85
potentiate other causes of disadvantage such as smoking, low
protein nutrition, and early age of first maternal pregnancy,
and child sexual abuse implying that cannabis use by disad-
Bones
vantaged groups compounds other functional deficits.112,114
Lower school age child IQ was also noted in another large
Cannabinoid receptors are present on bones. Physiological
longitudinal follow-up study.115 It is important to note, how-
For personal use only.
studies have shown that cannabinoids have an important role
ever, that such reductions in intellectual performance, execu-
in the regulation of bone density86; blockade or modulation of
tive function, memory, sustained attention, and verbal ability
CB1 cannabinoid activity protects from bone loss.87 Heavy
are also seen in samples of low-risk upper middle class
cannabis use in humans is associated with substantial bone
children of school age.116 Equally, it is important to note that
loss.54 Interestingly, CB2 stimulation appears to be causally
careful studies controlling for such pertinent confounding
associated with stimulation of both endosteal and periosteal
psychosocial variables find strong persistent effects of
bone growth by mechanisms involving inhibition of osteoclas-
cannabis exposure.117
togenesis, osteoblast stimulation, and favorable modulation of the
Maternal prenatal cannabis use has been found to predict
RANKL (receptor activated NF-kB ligand) - osteoprotegerin
later cannabis use during adolescence both as age of onset
system, matrix metalloproteinase inhibition, inhibition of
and frequency of use, a relationship that persisted after
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adrenergic sympathetic signaling to bone, and inhibition of
adjustment for many other risk factors.118
bone marrow monocyte-directed hemopoiesis88-99 (the bone
marrow-derived monocyte is believed to be the immediate
precursor of the multinucleate osteoclast). Cannabis use is
Genotoxicity, mutagenicity, and oncogenesis
also known to be associated with profound loss of alveolar
bone from the jaws,100-103 often in the context of severe
Cannabis use is associated with cancer of the lung30-32 (OR =
erosive periodontitis.104,105
2.3, 4.1, and 5.7), head and neck44,119 (OR = 4.1, 2.6, and
3.1), larynx (OR = 1.7 and 2.3), prostate (OR = 3.1)120, cervix
(OR = 1.4),120 testes (OR = 1.7),121 and brain (OR = 2.8).122
Maternal cannabis use and fetal development
Cannabis has also been linked with tumors of the urothelial
tracts.123-125 Several authors have also found evidence of a
Not all the studies in this field have returned results confirm-
dose-response relationship, either with dose, duration, or the
ing a link between maternal cannabis use and later deleterious
combined lifetime total duration of cannabis consump-
changes in the offspring.106 However, maternal cannabis use
tion.31,32,44,121 A report from Tunisia showed an eightfold rise
has been shown to reduce body weight at birth.107 Many birth
in lung cancer risk, but initially did not demonstrate a dose-
abnormalities were identified in a large Hawaiian sample
response relationship; tobacco is frequently mixed with can-
over 6 years. Of 54 birth defects studies, 39% were noted in
nabis in that country.30 A later expanded revision of these

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Clinical Toxicology vol. 47 no. 6 2009
520
A.S. Reece
data from the same area in northern Africa was able to
recently to be proportional to the age, the health, and the
demonstrate a relationship with the total dose duration of
reproductive fitness of stem cells in a variety of in vivo tissue
cannabis exposure.121
niches.145 It is of concern that the chromosomal damage was
Of great concern is the evidence of inheritable tumors such
shown in mice not only for tetrahydrocannabinol but also for
as childhood neuroblastoma (OR = 1.8, 4.7),126 rhabdomyosar-
cannabidiol (and cannabinol),140 a non-psychoactive cannab-
coma,45 and leukemia (OR = 11), particularly non-lymphoblastic
inoid that has been added to commercial cannabis sprays
leukemia,127 in cannabis-exposed pregnant mothers.
supposedly to confer safety!146
It should be noted that not all epidemiological studies have
The involvement of cannabinoids with at least three
been positive,128 with some studies failing to demonstrate
enzymes involved in DNA repair raises questions about their
such a link, possibly because cannabis exposure in the study
potential genetic toxicity, a subject that remains largely
population was limited.45 For example, a study conducted in
uninvestigated. Gonadal stem cell and genetic toxicity have
Los Angeles did not observe an association with lung cancer,
implications for cell growth inhibition, fetal malformations,
which the authors attributed to the relatively few cases
and inheritable defects including cancers. Indeed, evidence of
exposed to significant amounts of cannabis.129 Similarly, a
cannabis-induced altered DNA expression,147 a higher inci-
New Zealand study of head and neck cancer was recently
dence of 21 birth defects,107 and an 11-fold rise in inherited
found to be negative, a finding attributed by the authors to
leukemias in the offspring of cannabis users127 have been
uncontrolled confounding and inadequate sampling of the
documented. Other studies have produced similar findings,148
New Zealand population.128
including tissues of the germ line.149 The presence of such
Cannabinoids liberate radical species both by receptor
major chromosomal abnormalities in sperm cells but not in
binding (nitrogen-centered species130-132 ) and by uncoupling
circulating white blood cells149 is consistent with the inhibi-
mitochondrial oxidative phosphorylation via stimulation of
tion by cannabinoids of telomerase, which is well known to
the matrix protein uncoupling protein 2.133,134 Nitric oxide
be present in stem cells, germ cells, and cancer cells but not
generation at the cell membrane occurs via both CB1130 and
in the nuclei of normal tissue.150-152
non-CB1/2 receptor-mediated131 mechanisms. Indeed, it has
been shown that oxidation135 of the DNA base guanosine to
oxo-guanosine is a normal part of endocannabinoid signal-
Conclusions
ing. This potentially very serious and inherently mutagenic
defect is overcome during normal signaling by activation of
In summary, now there is evidence for the implication of can-
the base excision DNA repair pathway within cells. The
nabis in various psychiatric, respiratory, cardiovascular, and
For personal use only.
capacity of such DNA repair pathways is well known to be
bone pathologies.153,154 The reports of social disruption, dis-
limited, so the possibility exists that with pathological over-
organization, and deprivation consequent on widespread
stimulation, as might occur during substantial cannabis use,
heavy cannabis use from a number of communities around
the resulting major genetic defects would become fixed and
the world are of substantial concern. The features associated
eventually translated into altered mRNAs, micro-RNAs,
with chronic cannabis use imply that a clear public health
genetic expression, and protein sequences.
cautionary message is warranted along the lines employed for
Cannabis is known to stimulate the oncogenic MAP kinase
other environmental intoxicants such as tobacco, which
pathway,136 which is potently oncogenic, and to be involved
should be targeted strategically to young and otherwise vul-
particularly in the genesis of non-lymphocytic leukemias.137
nerable populations.
A strongly positive association between cannabis consump-
Clinical Toxicology Downloaded from www.informahealthcare.com by HINARI on 09/11/09
tion and this tumor has been found.127 Cannabinoids block
Declaration of interest: There is no conflict of interest to
topoisomerase II, an enzyme that untwists and makes accessi-
declare.
ble the dominant coding DNA strand and plays a vital role in
DNA repair, meiotic chromosomal replication, mRNA tran-
scription, and DNA hypermutation in prelymphocytes.138,139
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