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NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

tolerance to antinociception, and to anticonvulsant and locomotor effects
follow different time spans and occur to differing extents.
There is little evidence of withdrawal associated with cannabinoid use.
In fact, withdrawal reactions after prolonged use of cannabinoids are rarely
reported, probably because of the long half-life of cannabinoids, which
prevents the emergence of withdrawal symptoms. Increased release of
corticotrophin-releasing factor is a biochemical marker of stress that is
increased during cannabinoid withdrawal (Rodriguez de Fonseca et al.,
1997).

Neurobiological adaptations to prolonged use
Cannabis is sometimes regarded as an “innocuous” drug and the prevalence
of lifetime and regular use has increased. However, people with schizophrenia
who use cannabis are vulnerable to relapse and exacerbation of existing
symptoms, while users report short-lived adverse effects, and regular use is
related to the risk of dependence (Johns, 2001). Evidence linking cannabis to
irreversible brain lesions and the induction of toxic encephalopathy in
children is inconclusive.
It has been shown in several studies (as reviewed in Ameri, 1999) that
long-term exposure to cannabis can produce long-lasting cognitive
impairment, which may be due to residue drug in the brain, withdrawal
reaction or direct neurotoxicity of cannabinoids, tar, carboxyhaemoglobin
or benzopyrene. There is some evidence of impaired ability to focus
attention and filter out irrelevant information, which increases with the
number of years of use but is unrelated to frequency of use. The speed of
information processing is delayed significantly with increasing frequency
of use but is unaffected by duration of use. The results suggest that a chronic
build-up of cannabinoids produces both short-term and long-term
cognitive impairments (Solowij, Michie & Fox, 1995). In general, the data
support a drug residue effect on attention, psychomotor tasks, and short-
term memory during the 12–24 hour period immediately after cannabis use,
but evidence is as yet insufficient to support or refute either a more
prolonged drug residue effect, or a toxic effect on the central nervous system
that persists even after drug residues have left the body (Pope, Gruber
&Yurgelun-Todd, 1995).
A review of the preclinical literature suggests that both age during
exposure and duration of exposure may be critical determinants of
neurotoxicity. Cannabinoid administration for at least 3 months (8–10% of
a rat’s lifespan) was required to produce neurotoxic effects in peripubertal
rodents, which would be comparable to about 3 years of exposure in rhesus
monkeys and 7–10 years in humans. Studies of monkeys after having been
exposed daily for up to 12 months have not consistently reported
neurotoxicity, and the results of longer exposures have not yet been
published (Scallet, 1991).

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