Effects of alcohol (0.5 *) and MDMA (100 mg) on (simulated) driving performance, driving related performance and traffic safety

Movig et al., (2004) convincingly showed that drug use and especially multiple
drug use and drug-alcohol combinations among drivers is an important risk
factor for traffic accidents. Since drug- and medicine use is proportionally
increasing over the years, special efforts have to be directed towards gaining
better knowledge of the various aspects of this problem and developing
appropriate solutions. The objective of the recently started EU-project DRUID
(Driving under the Influence of Drugs, Alcohol and Medicines) is to give
scientific support to the EU transport policy (White Paper, 2001) by
establishing guidelines and measures to combat impaired driving.
In this protocol, a study is proposed to assess the performance effects
of single dose of (±) 3, 4-Methylenedioxymethamphetamine (MDMA, "ecstasy") and
a single dose of alcohol (0.5 *), and a combination of the two, on simulated
driving performance and driving related performance. A group of 20 experienced,
healthy frequent MDMA-users aged between 21 and 40 will be administered MDMA (0
and 100 mg) and alcohol (0 and 0.5 %0 ) according to a 4- way, double-blind,
placebo controlled, repeated measures, cross-over design. Performance
assessments will consist of simulated driving tasks and laboratory tests of
memory, response inhibition and impulsivity. The practical outcome of the
present study is to generate recommendations for the definition of analytical
and risk thresholds for driving under the influence of MDMA and the
MDMA-alcohol combination.
Driving performance is assessed on three levels: the strategically
level (general plans), manoeuvring level (controlled action patterns) and
control level (automatic action patterns; Michon, 1985). It expected that
alcohol will influence performance mainly on the control level expresed in an
increase the amount of swerving. The main negative effect of MDMA is expected
at the manoeuvring level. This will probably be expressed as an increase in the
amount of risk a subject is willing to take. For the alcohol -MDMA combination
it is expected that the stimulating effects of MDMA will moderate alcohol
induced effects on the control level. However the combination of the substances
will also lead to even greater impairment at the manoeuvring level as compared
to when substances are taken separately by inducing greater risk taking.

To assess the effects of single dose of 100 mg (±) 3,
4-Methylenedioxymethamphetamine (MDMA, "ecstasy") and/ or a single dose of
alcohol (0.5 %0) on simulated driving performance (in a controlled experimental
design).

To assess the effects of single dose of 100 mg (±) 3,
4-Methylenedioxymethamphetamine (MDMA, "ecstasy") and/ or a single dose of
alcohol (0.5 %0) on driving related tasks (cognitive tasks).

Generate recommendations for the definition of analytical and risk thresholds
for driving under the influence of MDMA alone or combined with alcohol for the
EU project DRUID.

The study will be conducted according to a double-blind, placebo-controlled,
4-way cross-over design with treatment orders counter-balanced according to a
Latin square. Driving tests will be conducted 1.5 hours post-drug oral intake
and 20 minutes post-alcohol oral intake. Cognitive and psychomotor tests will
be conducted directly after the driving tests approximately 2.5 hours post drug
intake.
The study will be conducted during an eight period in which 20 paid volunteers
will be subjected to four conditions. They will visit the UMCG four times with
a wash-out period of one week in between, and an introduction session,
including a dress-rehearsal test. The study will be conducted in a clinical
laboratory equipped with driving simulator.

Study conditions:
1 Matching placebo + alcohol-free drink
2 100 mg MDMA + alcohol-free drink
3 0.5 g/kg Alcohol + placebo
4 100 mg MDMA + 0.5 g/kg alcohol

The most serious acute somatic adverse effects of MDMA are hyperthermia,
hyponatermia and liver insufficiency. Hyperthermia can occur through inadequate
compensation of the centrally induced rise of core body temperature after MDMA
(Pennings et al., 1998). In a controlled experimental setting, it was shown
that subjects* body temperature rose significantly during MDMA intoxication,
independently of environmental temperature. However, the magnitude of elevation
was modest (between 0.3°-0.6C) (Freedman, Johanson, & Tancer, 2005). Other
factors though can cause an elevation of body temperature i.e. physical
activity (dancing) and concomitant use of other hypothermic drugs (e.g.
cocaine). Hyponatermia is also of central origin and is associated with the
demonstrated anti-diuretic hormone response by MDMA (Henry et al., 1998).
Hyponatermia is further facilitated by excessive fluid intake after MDMA.
Hyponatermia can be prevented by ascertaining that fluid intake after MDMA is
moderate and Natrium-containing (isotonic).
Liver insufficiency, hepatitis or fatal liver failure, appears to be a
rare idiosyncratic response to MDMA, which can even occur after a single dose.
The mechanism is unknown. Contamination of tablets, the origin of which is by
definition unclear in the practice of its illegal usage, can not be excluded
(de Man, Wilson, & Tjen, 1993; A. C. Parrott, 2004).
Transient subjectively experienced acute adverse effects of MDMA that
are reported most frequently (62%) include bruxism (teeth grinding), lack of
appetite, difficulty concentrating and impaired balance (Baylen & Rosenberg,
2006; Vollenweider, Gamma, Liechti, & Huber, 1998). Stimulant effects and
altered body sensations such as restless or heavy legs, paresthesias, increased
sensitivity to cold and hot flashes are less frequent (23-46%). Further acute
symptoms are thirst, palpitations and sweating. Compared to placebo, fatigue
and worries are reported less. Symptoms that may persist up to 24 hours in
23-46% of users are suppressed appetite, thirst, bruxism, feelings of
restlessness, difficulty in concentration and sweating, whereas after 24 hours
new subjective adverse effects consist of lack of energy, insomnia and brooding
in 23-46% of cases (Vollenweider et al., 1998).
It is known that in rats alcohol increases MDMA induced hyperactivity
but attenuates MDMA related hyperthermia (Hamida et al., 2007). Furthermore
plasma concentrations of MDMA can show a small increase after the use of
alcohol (Hernandez Lopez et. al. 2002).
Any serious adverse event, whether or not related to the study treatment will
be reported by the medical investigator immediately (within 24 hours) to the
principal investigator, the Medical Ethics Committee (MEC), the general
practitioner and the study subject. The exception to this rule is that serious
adverse events that have already been treated by the general practitioner or
medical specialist, or about which the general practitioner or medical
specialist have already been informed, which situation is to be judged by the
medical investigator, do not have to be reported to the general practitioner or
subject. A written report on the event will be sent to the MEC within three
working days.

Suspected unexpected serious adverse reactions

Advers events will be established by the principal investigator on basis of:
1. Answer to the open question: 'How are you feeling?'
2. Spontaneous reporting

Advers events will be classified under the responsibility of the medical
investigator. He/she will register his/her findings, conclusions and actions.
Intoxicated behaviour as a result of the intake of alcohol will not be reported
as an Advers events.