Marijuana, neurobiology, psychiatric and cognitive effects

Transcript

Diana De Ronchi, MD PhD
Ordinario di Psichiatria
Università di Bologna
Emailil
E
[email protected]
Marijuana,
neurobiology,
gy,
psychiatric
and cognitive
effects

Annual prevalence of 163 million or
3.9% of the global population
peak initiation occurred at age 18
within 10 years 8% of this group will
become marijuana dependent
Among new users, 1–2% will develop a
clinically
li i ll significant
i ifi
t cannabis
bi
dependence syndrome during the first
1–2 years after onset of smoking
Elkashef, et al, 2008
1

Marijuana use can have immediate
consequences.
940,953
940
953 emergency department (ED)
visits related to drug abuse in the
United States.
Marijuana was reported in 23% of those
visits (73 cases/100,000 population).

The marijuana plant (Cannabis sativa)
contains a total of 66 cannabinoids.
One of the major cannabinoids is
t t h d
tetrahydrocannabinol
bi l (THC)

behavioral and cardiovascular effects.
THC is rapidly absorbed following smoking,
with a PK similar to intravenous (i.v.)
administration.
In heavy users the average bioavailability is
23% and in light users 10%
2

THC is quickly distributed into tissues and
subsequently accumulated in body fat. THC
is metabolized rapidly, but the metabolites
are slowly eliminated. Approximately 80%
of the dose is excreted in 5 days, 65% in
feces and 20% in urine.
THC is metabolized primarily by CYP3A and
CYP2C;; over 80 metabolites have been
identified. Major metabolites include the
non-active THC-9-COOH and the
psychoactive 11-OH-THC.

Two cannabinoid receptors have been cloned. CB1
receptor is located in brain, spinal cord, and
peripheral tissue, while CB2 is in immune cells.
Endocannabinoids (anandamide) are natural
chemicals that activate CB1 receptors in the brain.
The system plays a physiological role in reward,
cognition, appetite control, and analgesia.
Chronic cannabinoid administration leads to
d
dependence.
d
C
Cannabinoid
bi id agonists
i t and
d
antagonists influence dependence on opioids,
alcohol, and nicotine.
3
PET summation
image in rhesus
brain following
injection of
[11C]MePPEP
]
Upper row: slice
including cerebellum
and medial and
lateral temporal
cortex. Middle row:
striatum, thalamus,
h l
and lateral temporal
cortex. Lower row:
prefrontal cortex
MR

PET images fused PET/MR
Yasuno, et al, 2008
Long-term heavy cannabis users: acutely intoxicated
every day
impairments in a variety of cognitive, perceptual, and
psychomotor tasks
short-term memory, sustained or divided attention,
complex decision-making, and reaction time
Ninety-seven
Ni
t
percentt off th
the h
heavy users reported
t d
driving on a regular basis while intoxicated
Kelly, et al, 2004
4

There is evidence from laboratory, simulator
and driving studies that the THC significantly
impairs driving performance.
tracking, attention, reaction time, short-term
memory, hand – eye coordination, vigilance,
time and distance perception, decision making
and concentration
Performance decrements are generally doserelated and typically persist for 2 –4 hours
Kelly, et al, 2004

Psychiatric problems
acute short-duration psychosis caused directly
by high-dose intoxication with cannabis (toxic
psychosis)
precipitation of clinically overt schizophrenia or
of relapse in previously well-compensated
schizophrenics
psychiatric comorbidity, i.e., psychiatric
problems that tend to occur together with
heavy cannabis use though not necessarily
caused by it
Kalant H, 2004
5

brief
psychotic
states after
heavy use
panic
reactions
acute anxietyy
or panic
major
depression
Kalant H, 2004
cannabis increases risk of psychotic outcomes
independently of confounding and transient
intoxication effects, although evidence for
affective outcomes is less strong.
there is now sufficient evidence to warn young
people that using cannabis could increase
their risk of developing
p g a psychotic
p y
illness later
in life
Moore, et al, 2007
6
Moore, et al, Lancet, 2007
• pooled analysis: an increase in risk of psychosis of 40% in
participants who had ever used cannabis
• most studies showing a 50–200% increase in risk for participants
who used most heavily
•A dose-response effect was observed in all studies that examined
the relation to increasing cannabis exposure
Moore, et al, 2007

The acute effects of synthetic intravenous THC
on psychosis, mood and cognitive functioning
THC-induced
THC
induced
phenomenology
particularly interesting
from the point of view of
a model psychosis, as
ideas of reference are
one of the commonest
symptoms in
schizophrenia
Morrison, et al, 2009
7
Bhattacharyya, et al, 2009

The correlation between the effects of THC on
activation in the ventral striatum and the
rostroanterior cingulate cortex and the
provocation of psychotic symptoms is
consistent with evidence that the striatum and
the cingulate are rich in cannabinoid
receptors.
The striatum and the cingulate have been
i li t d in
implicated
i the
th pathogenesis
th
i off psychotic
h ti
symptoms in schizophrenia
8

When individuals with genetic vulnerability for
schizophrenia use cannabis, they are either at
ultra-high risk for this disease or it initiates the
onset of the disorder that may inevitably occur
at a later time.
Since there is also extensive evidence that
schizophrenia is a brain disease likely
originating
g
g from developmental
p
anomalies in
both structure and corresponding brain
function, it seems logical that cannabis use on
top of an already compromised brain will lead
to psychosis.
DeLisi, 2008
9

It is more likely that cannabis users who
develop a transient psychotic episode
subsequent to heavy use may have only a
biochemical variant, such as low COMT *
activity, and thus higher dopamine that
would potentiate the effects of cannabis and
cause an acute psychotic reaction
*
Catechol-O-methyltransferase is an enzyme that
metabolizes dopamine, particularly in the prefrontal cortex
DeLisi, 2008
"Drug addiction is a brain disease that can be treated"
National Institute on Drug Abuse
10