Page 121 - Pagetit

NEUROSCIENCE OF PSYCHOACTIVE SUBSTANCE USE AND DEPENDENCE

Tolerance and withdrawal
Tolerance develops rapidly with use of ecstasy, and some individuals use
progressively larger amounts of ecstasy to reinforce its psychoactive effect
(McCann & Ricaurte, 1991; WHO, 2001). In some individuals, tolerance occurs
to the pleasant psychoactive effects of ecstasy but not to the physical collateral
effects, therefore any dose increase to augment the psychoactive effects may
produce dysphoria (Grispoon & Bakalar, 1986). In this group of individuals,
MDMA will not cause dependence, and thus the use of large amounts of
ecstasy for long periods is rare (Peroutka, 1989). It is still necessary to define
which are the social, genetic, cultural, environmental and hormonal factors
involved in these long-term individual differences in the effects of ecstasy.
For 2–3 days following MDMA use, there may be residual effects associated
with the acute withdrawal of the drug, including muscle stiffness and pain,
headache, nausea, loss of appetite, blurred vision, dry mouth and insomnia
(Kalant, 2001). Psychological effects may also be observed, most commonly
depression, anxiety, fatigue, and difficulty in concentrating (Kalant, 2001).
This is typical of the “crash” that is also seen following the use of ampheta-
mines and cocaine.

Neurobiological adaptations to prolonged use

Neurotoxicity induced by MDMA is cumulative and is related to the dose and
frequency of drug use (McKenna & Peroutka, 1990; Kalant, 2001). In animals,
acute neurochemical effects are observed after doses of around 5–10 mg/kg
of ecstasy and long-term effects occur after doses 4 times higher, or after
frequent administration of smaller doses. A neurotoxic schedule of ecstasy
reduces rat brain serotonin concentrations by 45%. Damage or
neuroadaptation to the brain has been clearly demonstrated in both humans
and in animal models, which show reduced serotonin concentrations,
neurons, transporters and terminals (Kalant, 2001).
There are also long-term psychiatric and physical problems associated with
MDMA use. Impairments of memory, decision-making and self-control are
observed, as are paranoia, depression and panic attacks (Kalant, 2001; Montoya
et al., 2002). There can also be major hepatic, cardiovascular and cerebral toxic
effects (Kalant, 2001; Montoya et al., 2002). The long-term depletion of brain
serotonin by ecstasy is also accompanied by impairment of body temperature
control and behavioural responses (Shankaran & Gudelsky, 1999). The public
health implications of these findings are apparent.

Volatile Solvents

Introduction
Several volatile chemicals (including gases such as nitric oxide, volatile
solvents such as toluene, and aliphatic nitrites) produce effects on the central

100

Chapter_4 100 19.1.2004, 11:43