The aim of the study was to investigate the effect of illicit stimulant use on tremor in healthy adults. The results suggest that abstinent ecstasy users exhibit an abnormally large tremor during movement. However, individuals with a history of use of amphetamine-like stimulants and cannabis exhibit normal tremor.
Tremor During Movement
In both types of movement, tremor was significantly larger in abstinent ecstasy users, but not in individuals that have previously used amphetamine-like stimulants and/or cannabis. The abnormally large tremor was observed in the physiological frequency range (7.4–13.3 Hz) and was robust given that statistical significance was observed for both peak and mean power. The abnormal tremor was also observed at frequencies lower (3.9–6.6 Hz) than the physiological range but statistical significance was only achieved in this range for auditory-paced movement. Data in the 0–3.9 Hz range was not investigated because voluntary movement occurred within this frequency range.
The abnormal tremor in the ecstasy group was surprising given that the majority of individuals in the group had minimal to moderate lifetime ecstasy use. Seven of the 9 subjects had used ecstasy on less than 20 occasions and 4 subjects had used ecstasy on 5–9 occasions (). Furthermore, subjects had been abstinent for an average of 3 months.
The mechanism that underlies abnormal tremor in abstinent ecstasy users is difficult to identify in humans. The result of our study suggests that the effect is not associated with the acute mechanism of action of ecstasy because all subjects had a negative urine screen for ecstasy and other drugs such as cocaine, amphetamine/methamphetamine, opiates, and benzodiazepines. The abnormal tremor in the ecstasy group was also not associated with subject characteristics such as age, height, weight, handedness, years of education, and speed of information processing because these parameters were well matched between groups. Neuropsychological performance was normal for individuals in the ecstasy group and symptoms of depression did not significantly differ between the ecstasy, amphetamine, and cannabis groups.
Evidence that suggests that ecstasy could play a specific role in abnormal tremor during movement comes from closer inspection of the amphetamine group. The amphetamine group consisted of individuals with a high lifetime use of amphetamine, and total stimulant use was significantly greater in the amphetamine group than in the ecstasy group (). Thus, any long lasting effect of amphetamine-like stimulants on tremor should have been apparent in this cohort. Any long lasting effect of alcohol and tobacco should also have been apparent in the amphetamine group because subjects in the amphetamine group tended to consume more alcohol and tobacco than subjects in the ecstasy group (). However, a factor that could have contributed to the absence of abnormal tremor in the amphetamine group is a longer duration of abstinence in the amphetamine group (5.5±6.5 yrs) than in the ecstasy group (0.3±0.3 yrs). However, both groups did include individuals with recent use.
Abnormal tremor in ecstasy users but not in individuals that have used amphetamine-like stimulants is surprising given that the mechanism of action of amphetamine, methamphetamine, cocaine, and therapeutic stimulants such as methylphenidate (e.g. Ritalin®) are more likely to alter brain regions involved in movement. These drugs cause acute, excess accumulation of primarily dopamine by disrupting synaptic vesicles, inhibiting monoamine oxidase, and/or blocking or reversing vesicular monoamine transporters and dopamine reuptake transporters 
. However, few studies have examined the association between use of these drugs and movement, although new cases of dystonia and tic disorders have been attributed to cocaine use 
and choreiform syndrome has been associated with amphetamine use 
. Abstinent methamphetamine users also exhibit poorer motor performance on timed gait and grooved pegboard tasks 
and epidemiological data suggests an increased risk (hazard ratio
2.65) of developing Parkinson’s disease later in life 
How Might Ecstasy Affect Tremor During Movement?
Tremor during movement is thought to arise primarily from pulsatile control of agonist and antagonist muscles 
and central oscillations in brain activity 
. However, motor unit discharge properties and activity in muscle stretch reflex pathways also contribute to the peak observed in the physiological range 
Animal studies show that MDMA, the main psychoactive ingredient of ecstasy tablets, affects brain structures that are involved in tremor and movement. MDMA binds to pre-synaptic monoamine reuptake transporters causing acute accumulation of 5-HT and noradrenaline, and to a lesser extent dopamine 
. Excessive accumulation of 5-HT and/or peripheral formation of toxic MDMA metabolites leads to neurotoxicity in serotonergic nerve terminals 
. Other long-term effects include depletion of 5-HT and tryptophan hydroxylase (rate limiting enzyme in 5-HT synthesis), and decreased SERT density in rats 
, non-human primates 
, and humans 
. Long-lasting serotonergic dysfunction has been observed in the basal ganglia (striatum), thalamus, and cerebral cortex 
. These brain regions play an important role in tremor and movement and exhibit central oscillatory activity 
. The amplitude of central oscillatory activity could be increased in abstinent ecstasy users. This theory is supported by the results of an electroencephalography (EEG) study in humans that showed a global increase in the alpha rhythm (8–12 Hz) that is positively correlated with increasing extent of ecstasy use 
. Furthermore, use of electromagnetic tomography has demonstrated acute changes in the spatial distribution of electrical activity within the brain following a single dose of ecstasy 
There are a small number of case studies that also suggest a possible link between ecstasy use and tremor. Ecstasy use has been associated with acute dystonic reaction in the neck and coarse action tremor in the upper limb (
) and postural tremor 10 days after ecstasy intoxication 
. Furthermore, use of selective serotonin reuptake inhibitors (e.g. fluoxetine), serotonin and norepinephrine reuptake inhibitors (e.g. venlafaxine), and tricyclic antidepressants (e.g. amitriptyline) is associated with abnormal tremor in patients undergoing treatment for depression 
It is not known if the abnormal tremor observed in the ecstasy group will persist or improve over time. Recovery of serotonin reuptake transporters has been observed in humans after 12 months of abstinence 
and axonal sprouting of 5-HT neurons (i.e. re-innervation) has also been observed in rats and non-human primates after 12–18 months of MDMA abstinence 
. However, abnormal re-innervation patterns occur in non-human primates suggesting that recovery of serotonergic neurons in human ecstasy users may be limited 
It is also difficult to investigate the relation between ecstasy dose and the amplitude of tremor during movement. The difficulty arises from variability in the amount of MDMA present in ecstasy tablets (0–250 mg) and the potential presence of other compounds that may affect tremor. In Adelaide, Australia, where the current study was performed, recent chemical analysis of ecstasy tablets suggests that MDMA is the major constituent in 85% of tablets (25–75 mg per tablet) and 50% of tablets contain 100% MDMA 
. Hence, it is likely that a significant proportion of ecstasy users in the current study were exposed to effective, and possibly neurotoxic, doses of MDMA. Regardless of the actual content of the ecstasy tablets, it appears that individuals who have consumed ecstasy tablets in Australia exhibit an abnormally large tremor during movement.
A limitation of the current study was that postural tremor was not investigated. Assessment of postural tremor is routinely performed during neurological examinations and objective measurement of postural tremor in abstinent ecstasy users is required to provide further clinical relevance for the current findings. An additional limitation is that it is unknown if subjects in the ecstasy group had a pre-existing tremor prior to the onset of illicit drug use.
Tremor During Relaxation
Resting tremor was unaltered in the ecstasy, amphetamine, and cannabis groups both in the physiological frequency range and at lower frequencies. The result of our study contradicts the findings of an earlier study conducted on abstinent cocaine dependent individuals. Abstinent cocaine-dependent individuals are reported to exhibit an increased resting tremor that occurs at an abnormally low frequency 
. The contradictory findings are likely due to differences in spectral analysis methodology and uncertainty regarding total stimulant use or use of other types of illicit drugs in the Bauer (1993) study.
In summary, our results suggest that individuals with a history of ecstasy use exhibit an abnormally large tremor during movement that may persist for months after cessation of use. In light of the increasing popularity of ecstasy, further investigation of the long-term neurotoxic and functional consequences of ecstasy use is warranted. Future studies are also required to determine if abnormal tremor during movement translates to increased risk of movement disorders in this population.