Long-term effects of exposure to cannabisLeslie Iversen
The long-term use of cannabis, particularly at high intake levels,
heavy users of cannabis, or in animals treated for prolonged
is associated with several adverse psychosocial features,
periods with the drug. Most reports have shown that there
including lower educational achievement and, in some
are deficits in the performance of complex cognitive
instances, psychiatric illness. There is little evidence,
tasks in long-term cannabis users, although there is little
however, that long-term cannabis use causes permanent
evidence that these are qualitatively or quantitatively
cognitive impairment, nor is there is any clear cause and effect
more severe than those seen after acute drug use .
relationship to explain the psychosocial associations. Thereare some physical health risks, particularly the possibility of
More controversial is the question of whether long-term
damage to the airways in cannabis smokers. Overall, by
cannabis use can cause irreversible deficits in higher brain
comparison with other drugs used mainly for ‘recreational'
function that persist after drug use stops. Human studies
purposes, cannabis could be rated to be a relatively safe drug.
are fraught with difficulties, as described in detail byEarleywine Indeed, many studies have suffered from
poor design. One confounding factor in human studies is
University of Oxford, Department of Pharmacology, Mansfield Road,
that comparisons have to be made between groups of drug
Oxford OX1 3QT, UK
users versus non-users; however, it is usually impossible
Corresponding author: Iversen L ([email protected]
to compare the baseline performance of these groupsbefore cannabis use to see if they are properly matched.
Pope et al. for example, tested 69 early-onset heavy
Current Opinion in Pharmacology 2005, 5:69–72
cannabis users (who began smoking before the age of 17)
This review comes from a themed issue on
in a battery of neuropsychological tests after a two-week
period of abstinence. The group performed significantly
Edited by Graeme Henderson, Hilary Little and Jenny Morton
worse than late-onset users or controls, but also displayeda lower verbal IQ. When the data were adjusted for this,
Available online 21st December 2004
all differences between early-onset users and others
1471-4892/$ – see front matter
ceased to be significant.
# 2005 Elsevier Ltd. All rights reserved.
It is not sufficient to identify a group of cannabis users and
simply to test them after stopping cannabis use. Onestudy, for example, recruited 63 current heavy users who
had smoked cannabis at least 5000 times in their lives and
72 control subjects . The subjects underwent a 28-daywashout from cannabis use, monitored by urine assays. At
days 0, 1 and 7, the heavy users scored significantly below
Cannabis is the most commonly used illicit drug. In many
control subjects on a battery of neuropsychological tests,
countries, more than 50% of young people have used it at
particularly in recall of word lists. However, by day 28,
least once and it is widely perceived as relatively safe.
there were no differences between the groups in any of
Many people believe that there are genuine medical uses
the test results, and no significant association between
for cannabis-based medicines and it seems likely that
cumulative lifetime cannabis use and test scores. The fact
such products will gain official approval in several
that drug-induced effects on cognitive performance can
Western countries. Concurrently, there is a move towards
persist for up to a week after stopping the drug (perhaps
relaxation of the criminal penalties associated with the
because of the persistence of D9-tetrahydrocannabinol
recreational use of cannabis — ranging from the down-
[THC] in the body, or because of a subtle withdrawal
grading of criminal penalties in the UK to the possibility
syndrome) means that many earlier studies that did not
of full legalization in Canada and Switzerland. In light of
allow a sufficiently long washout period might be invalid.
these changes in attitude, it is timely to consider again theadverse effects associated with long-term cannabis use
One way of assessing cognitive function is to measure IQ.
over a period of years, as no drug can ever be considered
Fried et al. tested the effects of cannabis use in a group
of 70 young people by subtracting each person's IQ scoreat nine years of age (before drug use) from their score at
Effects on cognition
age 17-20 years. Current cannabis use was found to be
Several studies have addressed the question of whether
significantly correlated in a dose-dependent manner with
severe deficits in cognitive function develop in chronic
a decline in IQ scores. However, no such decline was seen
Current Opinion in Pharmacology 2005, 5:69–72
in subjects who had formerly been heavy cannabis users
cannabis use can precipitate psychiatric illness in a vul-
and had stopped taking the drug. The authors concluded
nerable minority of previously well people remains unan-
that cannabis does not have a long-term effect on global
swered. One could equally argue that a tendency to
psychotic illness might increase the likelihood of earlycannabis use . It is possible that cannabis may pre-
This general conclusion was also supported by a review of
cipitate schizophrenic illness earlier in vulnerable people
the 40 published studies that met adequate criteria, which
who exhibit ‘schizophreniform' tendencies. Such a con-
failed to detect any consistent evidence of persisting
clusion is supported by the results of a study of 122 newly
neuropsychological deficits in cannabis users — although
admitted schizophrenia patients in the Netherlands,
some studies reported subtle impairments in the ability to
which showed a strong association between cannabis
learn and remember new information
use and the age of onset of the first psychotic episodein men, with users experiencing their first psychotic
Cannabis and psychiatric illness
episode 6.9 years earlier than non-users
There has been a long-standing concern that cannabis usemight precipitate mental illness in some users. It is clear
Other studies have explored the association between
that an acute schizophrenia-like psychosis can occur in
cannabis use and depression. One longitudinal study in
response to a high dose of cannabis , but whether
Australia reported that daily use of cannabis by teenage
cannabis use can cause persistent psychiatric illness in
girls (but not boys) led to an approximately twofold
people who had not previously shown psychotic symp-
increased risk for depression/anxiety in later life A
toms remains contentious. A recent re-analysis of the
review of other studies of this type suggested that heavy
results of a large scale study of >50 000 Swedish men
cannabis use may increase depressive symptoms in some
(age 18–20 years) conscripted into the Swedish army
users, but whether this represents a causal relationship is
between 1969 and 1970 suggested that those who had
used cannabis >50 times before the age of 18 years had a6.7-fold increased risk of developing schizophrenia in
Psychosocial sequelae of cannabis use
later life . A review of this and four other longitudinal
Apart from the potential risk of mental illness, there has
cohort studies also concluded that early cannabis use
been a long standing concern that adolescent use of
might be a causal factor for schizophrenia-like illness
cannabis could lead to reduced educational achievement
in later life However, the interpretation of such
and reduced motivation — sometimes referred to as an
studies is fraught with many difficulties, as reviewed by
Macleod et al. These authors highlighted that proofof a causal relationship is subject to many confounding
Cherek et al. attempted to assess this experimentally
factors. When known confounding factors were applied to
in a study in which human participants earned money by
the Swedish army data, for example, the odds ratio was
responding on a complex lever-pressing schedule. There
reduced from 6.7 to 3.1 This, in turn, suggests that
was a significant reduction in the number of responses,
other residual unidentified confounding factors are also
time spent and money earned when the subjects were re-
likely to exist. The published studies show that the
tested while smoking cannabis, indicating a drug-induced
existence of ‘prodromal' symptoms of psychosis clearly
reduction in motivation.
increased the risk of subsequent psychiatric illness incannabis users . This factor was adequately con-
Various longitudinal studies have sought to establish the
trolled for in only one of the five published longitudinal
relationship between cannabis use and subsequent edu-
studies In this New Zealand cohort, even when
cational achievement. A study of 1265 New Zealand
those exhibiting prodromal symptoms of psychosis were
children showed that cannabis use was dose-depen-
eliminated, those who started cannabis use by age 15
dently related to an increased risk of leaving school
years (but not those who started later) showed a fourfold
without qualifications, failure to enter university and
increase in the risk of developing schizophrenia-like ill-
failure to obtain a university degree. A similar conclusion
ness by age 26 years. However, the number of subjects
was reached in reviews of other published studies of this
involved was small (there were 26 15-year old cannabis
type . The review by Macleod et al. was
users, of whom three developed mental illness) so the
particularly comprehensive; the authors studied 48 pub-
statistical power of this study was limited. Degenhardt
lished longitudinal studies on the use of cannabis, of
et al. sought to test the hypothesis of a causal relation-
which 16 were considered to provide the most robust
ship between cannabis use and schizophrenia by a care-
evidence. Their conclusions for cannabis use were, firstly,
ful examination of the incidence of schizophrenia in
Australia during the past 30 years. Although the preva-
achievement; secondly, a consistent association with
lence of cannabis use had increased markedly during this
use of other drugs; thirdly, an inconsistent association
period, there was no evidence of a significant increase in
with psychological problems of various types; and finally,
the incidence of schizophrenia. The question of whether
an inconsistent association with antisocial or other
Current Opinion in Pharmacology 2005, 5:69–72
Long-term effects of exposure to cannabis Iversen
problematic behaviours. They concluded that ‘‘Available
nity, there is no evidence that cannabis causes any other
evidence does not support an important causal relation
serious immunosupression in users . The authors sug-
between cannabis use and psychosocial harm, but cannot
gested that the effects on lung macrophages might be
exclude the possibility that such a relation exists''.
related to the ability of cannabis in animal studies to causea shift from Th1 to Th2 cytokine production.
Whatever the nature of the association, it seems clear thatlong-term heavy cannabis use carries a variety of negative
With increasing use of cannabis, there remains a concern
attributes. A case control study compared 108 heavy-use
that cannabis use during pregnancy might impair foetal
long-term cannabis users, who had on average smoked
development. Reviews of data from humans, however,
18 000 times, with 72 age-matched controls who had
suggest that such effects are minimal for cannabis users
smoked cannabis <50 times The heavy-use can-
when compared with the well-documented adverse
nabis smokers reported significantly lower educational
effects of tobacco or alcohol use Nevertheless,
attainment and lower income than did controls. When
treatment of pregnant rats with high doses of THC did
asked to rate the subjective effects of cannabis on cogni-
lead to significant reductions in expression of neural
tion, memory, career, social life, physical and mental
adhesion molecule L1 in the foetal brain — a key protein
health and various quality-of-life measures, a large major-
for brain development
ity of heavy-use cannabis smokers reported negativeeffects of their drug use.
ConclusionsA review of the literature suggests that the majority of
Cannabis and substance dependence
cannabis users, who use the drug occasionally rather than
Although it was previously thought that cannabis was not
on a daily basis, will not suffer any lasting physical or
a drug of addiction, it is now recognized that cannabis use
mental harm. Conversely, as with other ‘recreational'
can lead to substance dependence in perhaps as many as
drugs, there will be some who suffer adverse conse-
10% of regular users, according to the internationally
quences from their use of cannabis. Some individuals
accepted DSMIV definition of ‘substance dependence'
who have psychotic thought tendencies might risk pre-
. In both animals and humans, a clear withdrawal
cipitating psychotic illness. Those who consume large
syndrome can be identified In rodents, chronic
doses of the drug on a regular basis are likely to have lower
administration of THC or synthetic cannabinoids leads
educational achievement and lower income, and may
to downregulation and desensitization of cannabinoid
suffer physical damage to the airways. They also run a
CB1 receptors in the brain This might partly explain
significant risk of becoming dependent upon continuing
the tolerance that develops in both animals and humans
use of the drug. There is little evidence, however, that
on repeated use of the drug. In regular cannabis users,
these adverse effects persist after drug use stops or that
abstinence leads to a withdrawal syndrome characterized
any direct cause and effect relationships are involved.
by negative mood (irritability, anxiety, misery), musclepain, chills, sleep disturbance and decreased appetite. A
In contrast, cannabis might have beneficial effects in
placebo-controlled study showed that these symptoms
some medical indications. There is considerable litera-
were significantly reduced by oral administration of THC,
ture obtained from animal studies to suggest that cannabis
suggesting that the withdrawal syndrome and underlying
has analgesic effects . Until recently, however, there
substance dependence were related to effects of THC on
has been a dearth of controlled clinical studies to validate
the cannabinoid CB1 receptor, rather than to any other
such effects in patients. This has now changed, with the
component of herbal cannabis .
publication in the past two years of a number of double-blind placebo-controlled trials showing the effectiveness
Other potentially toxic effects of long-term
of cannabinoids in relieving chronic neuropathic pain
or pain associated with multiple sclerosis
Some of the most serious adverse effects of smoked
. The largest of these trials involved 630 multiple
cannabis are on the respiratory system. Although little
sclerosis patients and showed significant pain relief after
progress has been made recently in quantifying such
15 weeks of treatment with either pure THC or cannabis
risks, warnings continue to be issued about the potential
extract It seems likely that medicinal cannabis will
for long-term damage or even malignancy in the airways
re-enter the Pharmacopoeia.
It is known that lung macrophages isolated fromcannabis smokers exhibit impaired anti-bacterial activity,
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SIGA LA DAMA, SIGA EL CABALLERO Dibujo animado Septiembre 27 del 2013 01. Guion Literario Siga la dama, siga el caballero I. Idea matriz Una decepción amorosa lleva a un hombre a cometer un crimen pasional Tuerca, un payaso de restaurante lleva una vida rutinaria y aburrida hasta que conoce a Jalea, otra payaso de restaurante, con la que consuma un fugaz y tórrido romance. Mientras Tuerca queda profundamente enamorado, Jalea no le da mayor importancia a lo acontecido y rápidamente encuentra afecto en un mimo callejero. Al darse cuenta que fue sustituido, Tuerca cae en una profunda depresión que al no poder sobre-llevar lo empuja a cometer un crimen pasional.
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