185 ADICCIONES, 2010 · VOL. 22 NÚM. 3 · PÁGS. 185-190
Marijuana is consistently the most widely used illicit drug among
teenagers and most users first experiment it in adolescence. Adolescence
is a critical period between childhood and adulthood, including not
only reproductive maturation, but also cognitive, emotional and
social maturation. In this period adolescent brain is still in transition
differing anatomically and neurochemically from the adult’s one.
The endocannabinoid system is an important determinant for
cerebral maturation, therefore its strong stimulation by the delta-9-
tetrahydrocannabinol, that acts through the endocannabinoid system,
might lead to subtle but lasting neurobiological changes that can
affect adult brain functions and behaviour. We summarize the more
recent researches investigating the relationships between adolescent
exposure to cannabinoids and increased risk for psychotic disease such
as schizophrenia, as highlighted by both human and animal studies.
Epidemiological evidence suggests that cannabis use is a risk factor for
schizophrenia, and an exacerbation of symptoms and worsening of the
schizophrenic prognosis may occur in individuals with a predisposition
for schizophrenia. The characteristic of adolescent brain probably makes
it more vulnerable to cannabis effect producing psychotic like symptoms
and possibly cause schizophrenia.
Key words: Cannabis, adolescence, psychosis, schizophrenia, brain
La marihuana es la droga ilegal más utilizada entre los adoles-
centes. La mayoría de los usuarios comienzan además a expe-
rimentar con ella durante este período. La adolescencia es una
etapa crítica, que incluye no sólo la maduración reproductiva,
sino también la cognitiva, emocional y social de maduración.
El cerebro del adolescente está aún en transición, difiriendo
tanto anatómica como neuroquimicamente del adulto. El sis-
tema endocannabinoide es un determinante importante para
la maduración cerebral, por lo que su importante estimulación
a través del delta-9-tetrahidrocannabinol, que actúa a través
del sistema endocannabinoide, podría conducir a cambios neu-
robiológicos sutiles pero duraderos, que pueden afectar las
funciones cerebrales y el comportamiento incluso cuando ya
es adulto. Resumimos las más recientes investigaciones acerca
de la exposición de los adolescentes a los cannabinoides y el
riesgo de trastornos psicóticos como la esquizofrenia, como se
desprende de los estudios tanto humanos como animales. La
evidencia epidemiológica sugiere que el consumo de cannabis
es un factor de riesgo para la esquizofrenia, y contibuye a la
exacerbación de los síntomas y al empeoramiento del pronós-
tico en individuos con predisposición. Las características del
cerebro adolescente, probablemente lo hace más vulnerable a
los efectos del cannabis produciendo síntomas similares a los
psicóticos y posiblemente causando la esquizofrenia.
Palabras claves: cannabis, adolescencia, psicosis, esquizofrenia, cerebro.
Enviar correspondencia a:
DBSF and Center of Neuroscience. University of Insubria.
Via A. da Giussano 10, 21052 Busto Arsizio (Varese), Italy.
Consumo de cánnabis de los adolescentes y esquizofrenia:
evidencias epidemiológicas y experimentales
Adolescent cannabis consumption and schizophrenia:
epidemiological and experimental evidences
Consumo de cánnabis de los adolescentes y esquizofrenia: evidencias epidemiológicas y experimentales
The endocannbinoid system
CB1 and CB2 receptors, their endogenous lipid ligands,
the endocannabinoids (ECs), and associated proteins
(transporters, biosynthetic and degradative enzymes). The
cannabinoid CB1 receptor is a presynaptic receptor widely
expressed throughout the brain and present at lower density
in peripheral tissues, whereas CB2 receptor is predominately
located in immune cells and in tissues such as the spleen
and liver, although there is evidence for the presence of
cannabinoid CB2 receptors in the brain1.
he endocannabinoid system is a recently discovered
signalling system located in both brain and periphery1.
It comprises the G-protein coupled cannabinoid
The two primary endogenous ligands which have
been characterized as endocannabinoids are the
N-arachidonoylethanolamine, or anandamide (AEA),
and 2-arachidonoylglycerol (2-AG). Both AEA and 2-AG
are synthesized post-synaptically from phospholipid
precursors through activity-dependent activation of specific
phospholipase enzymes. AEA is hydrolyzed by the enzyme
fatty acid amide hydrolase (FAAH), generating arachidonic
acid and ethanolamine, while 2-AG is primarily metabolized
by monoacylglycerol lipase (MAG lipase), which results in the
formation of arachidonic acid and glycerol.
The endocannabinoid signalling acts differently from
most neurotransmitter systems and endocannabinoids
are released “on demand” by post-synaptic cells, acting as
retrograde messengers and traverse back across the synapse
where they bind to pre-synaptically located CB1 receptors
reducing synaptic transmitter release.
Endocannabinoid signalling has been found to be present
during the gestational period and several studies have
been focused on the relevance of this system for neural
developmental processes. During early phases of neuronal
development, endocannabinoid signalling is fundamental
for the proliferation and differentiation of progenitor
cells, axonal guidance, neuronal migration, fasciculation,
positioning of cortical interneurons, neurite outgrowth and
morphogenesis2,3. A series of important aberration have
been described to occur following disruption of normal
endocannabinoid signalling during ontogenetic phases.
Adolescence refers to the developmental time period
between childhood and adulthood, and in humans is
generally considered to encompass the ages of 12 to 17.
Brain maturation continues into adolescence and the precise
role of endocannabinoid signalling during the adolescence
has not been experimentally elucidated yet but is reasonable
that the neurodevelopmental and morphogenic roles of
endocannabinoids persist in adolescence. This hypothesis
is reinforced by the dynamic changes that occur in the
ontogenetic development of the endocannabinoid system
during adolescence. In this view a strong stimulation of the
endocannabinoid system through cannabis consumption
during adolescence may disrupt the normal endocannabinoid
signalling producing long-standing consequences on adult
Schizophrenia: human studies
A number of studies have investigated whether exposure
to cannabis during adolescence may represent a risk factor
for developing psychotic disorders such as schizophrenia4,5.
A longitudinal study, performed in Dunedin (New Zealand),
highlighted that cannabis users by age 15 and 18 had
more schizophrenic symptoms compared to controls (never
smoked cannabis or had used cannabis “once or twice”) at
age 26. Moreover, earlier use at age 15 conferred a greater
risk of schizophrenia outcomes than later use. In contrast, a
systematic review of longitudinal studies published in 2004
failed to demonstrate a causal relationship between cannabis
in adolescence and psychosocial harm, but could not exclude
the possibility that such a relation exists6.
More recently, in Zurich (Switzerland), an increase in first
admission rates of patients with schizophrenia and other
psychotic disorder was observed in the second half of the
1990s in males aged between 15 and 197. Concomitantly,
there was an increase in the use of cannabis among 15 to
16 year old Swiss boys from 15% in 1990 to 41% in 1998,
suggesting that this may be the reason for the higher
admission rates. In another study performed in Greece and
enrolling 3.500 19-years teenagers, the use of cannabis
in adolescence was positively associated with both the
positive and negative symptoms of schizophrenia, strongly
highlighting that cannabis represents a risk factor for the
development of schizophrenia when used in adolescence8.
Accordingly, adolescent of 15 to 16 year old who had
smoked cannabis presented more likely or more symptoms
of psychosis when compared to non smokers. Finally, two
studies have found increased schizotypy among american
undergraduate college students (mean age 21.7 years) and
English University students (mean age 22 years) who used
Sugranyes et al11 recently confirmed that cannabis
use was significantly associated with a decrease in age of
onset of schizophrenia and this is of particular relevance
considering that it has been proved that the early onset of
schizophrenia is a negative outcome factor. A study in Spain
enrolling patients with first episode psychosis (average
age 15.5 years) showed a higher rate of positive symptoms
and less negative symptoms and these episodes were more
frequently observed in cannabis smokers compared with non
Summarizing, several studies suggest the presence
of a causal link between adolescent cannabis use and
the development of psychosis such as schizophrenia.
The discrepancies between epidemiological studies can
be ascribed to variability in the evaluation of psychotic
symptoms and in the control of confounding factors.
There is urgent need for multidisciplinary research
approaches, to build a scientific-based opinion on the long-
lasting consequences of cannabis use in adolescence, and
the results might impact the quality of basic knowledge and
its translation at human level.
Despite the increasing use of cannabis among
adolescents, experimental studies focused on long-lasting
effects of adolescent cannabinoid exposure on psychosis-
related behaviours in adult rodents are very scarce12. The
experimental models currently available suffer several
limitations and often represent only certain aspects of the
pathology, making it difficult to translate the findings to the
Several papers are focused on the effect of adolescence
exposure on cognitive performance. Adolescent exposure
to synthetic or natural cannabinoid agonists has been
reported to induce impairments in object recognition
memory at adulthood in both male and female rats and
in spatial working memory without affect other forms of
memory (aversive memory or spatial learning)13,14. Moreover
adolescent exposure to THC worsened the cognitive
impairment induced by intermittent chronic administration
of phencyclidine, an animal model of schizophrenia-like
cognitive deficit15. In contrast the co-treatment with the CB1
receptor antagonist AM251 recovered it16.
Only few papers dealt with the relationship between
adolescent cannabis use and vulnerability to other
schizophrenia-like symptoms in adulthood. Schneider and
Koch13,14 using male rats treated with synthetic WIN5521-2,
observed a deficit in the prepulse inhibition of the startle
reflex (PPI), when tested in adulthood. Chronic treatment
with THC or the synthetic cannabinoid CP-55,940 during
adolescence induced a significant decrease in social
behaviour measured in the social interaction test17. Adult
rats exposed to WIN 55,212-2 during adolescence showed
a significant increase in locomotor activity when tested in
the open field. Furthermore, THC worsens disruption of PPI
induced by isolation rearing, but has no effect on PPI in rats
that are not socially isolated18.
The molecular and cellular mechanisms by which
adolescent exposure to cannabinoids favour the
probability to develop schizophrenia-like symptoms are
still unclear. Interestingly, when an animal model used to
induce schizophrenia-like symptoms was used during the
periadolescent period, a decrease in CB1 receptor expression
and/or G protein coupling has been observed in cerebral
areas relevant to schizophrenia. Reciprocal increase in FAAH
and decrease CB1 receptor expression was present in the
caudate putamen of socially isolated rats19, an environmental
model of schizophrenia and a specific increase in 2-AG levels
was measured in the PFC of rats chronically treated with
phencyclidine (PCP), associated with reduced functionality
of the CB1 receptor in this brain area15. In line with this, in
the hippocampus of maternally deprived rats a decrease in
CB1 receptor expression and an increase in 2-AG levels have
Moreover, adolescent THC exposure in male rats
provoked lasting changes in the hippocampal protein
expression profiles related to degenerative and oxidative
changes as well as impairment in plasticity of both neurons
and glia in this brain region, accompanied by a reduction
in dendrite length and complexity and number of dendritic
spines in the dentate gyrus20. In female rats, adolescent THC
exposure induced in the PFC a reduction in synaptic density
and/or efficiency21. Therefore, adolescent cannabinoid
exposure triggers a plethora of cellular and molecular events
in the brain that could be involved in the development of the
different symptoms of schizophrenia.
Recently also an increase in CB2 receptor expression
in hippocampal regions of maternal deprived rats was
observed22. The authors suggested a role for CB2 receptors
in the psychotic like behavioral alterations observed in this
animal model. Moreover, Ishiguro and colleagues23 described
a polymorphism in the gene encoding for CB2 receptors
associated with schizophrenia in a Japanese population.
Additionally, administration of the CB2 receptor antagonist
worsened disruption of PPI induced by the NMDA receptor
antagonist MK-801 in rats. Thus, CB2 receptors could be
another actor involved in psychotic like symptoms associated
with cannabis consumption.
The mechanism by which adolescent cannabis
consumption could increase the susceptibility to psychoses
such as schizophrenia is still unclear. Recent studies
have found that endocannabinoid system is implicated in
schizophrenia and post mortem alteration in CB1 receptor
have been observed in brain of schizophrenic patients
in some studies. Taken together, these observations
indicate a dysregulation of the endocannabinoid system in
schizophrenia and suggest an “endocannabinoid hypothesis
Furthermore, it has been suggested that the endo-
cannabinoid system may act as a protective mechanism
whereby endocannabinoids are released in response to
an hyperdopaminergic state in an attempt to decrease
dopaminergic transmission24,25. Thus, it is possible that
repeated use of cannabis in adolescence leads to sensitization
of the endogenous mesolimbic dopaminergic system and this
is why cannabis use during adolescence results in a worse
outcome with respect to development of schizophrenia
compared with ingesting cannabis during adulthood.
In the last 5 years a number of studies has highlighted
that an increased risk of developing adult psychosis exists
in patients with the COMT Valine polymorphism following
adolescent cannabis exposure. These authors suggested that
the observed gene x environment interaction may be limited
to a sensitive period of brain development in adolescence26.
However, this was not replicated in a cohort of approximately
500 UK patients with schizophrenia.
Finally, it may be remembered that the frequency and
amount of cannabis consumed in addition to the different
forms of preparation are variable factors that are difficult
to take into account. Moreover, the amount of the major
psychoactive constituent THC varies in the different
cannabis varieties ranging from the classical 2% to 20% in
some preparation. In addition, the concentration of other
Consumo de cánnabis de los adolescentes y esquizofrenia: evidencias epidemiológicas y experimentales
cannabinoids in cannabis preparations may be important
in determining the susceptibility to schizophrenia following
cannabis use. In fact, animal studies as well as clinical studies
show that the non psychoactive constituent cannabidiol has
antipsychotic activity27,28. In addition, it has been suggested
that cannabidiol may protect against some Pro-psychotic
effects of THC27.
The neurodevelopmental characteristic of adolescence
probably creates a more vulnerable circumstance for
cannabis to produce psychotic-like symptoms and possibly
cause schizophrenia. Epidemiological data suggest
that cannabis abuse is a risk factor for the onset of
schizophrenia and, in individuals with a predisposition
for schizophrenia, the ingestion of cannabis exacerbates
symptoms and worsens the schizophrenic prognosis. Due
to the important role of the endocannabinoid system in
moderating adolescent neurodevelopmental processes, we
can speculate that adolescent exposure to cannabinoids
might alter the normal developmental neuronal processes
involved in brain maturation, thus leading to a predisposition
to develop schizophrenia, possibly inducing dysfunction
in the more relevant neurotransmitter systems such as
GABAergic and dopaminergic transmission. Moreover, some
adolescents possess a genetic vulnerability in the COMT
gene that makes them more susceptible to the pro-psychotic
effects of cannabis. To further investigate the role of the
endocannabinoid system in neurodevelopment, as well as
molecular and neurochemical consequences of adolescent
cannabinoid exposure, preclinical studies are needed to
enhance our knowledge on the link between adolescent use
of cannabis and schizophrenia.
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