Results with the elevated plus maze have produced discrepant outcomes both between 17,60,65,96,106 and within 118,119 laboratories. There have been findings of an increase 60,106, decrease 96, or no appreciable change 17,65 in anxiety-like behavior in adult rats. A three day treatment regimen (PD 28–30) caused no significant effects when rats were assessed in early adulthood 16,17. Repeated administration from PD 35 to 60, also in rats, resulted in increased open-arm exploration 119 or hyperactivity 118 which appears to depend on the dosing regimen although the inherent unreliability of this test 32 could also be a factor. An anxiogenic pattern in the emergence test has been consistently identified several weeks after adult MDMA treatments to Wistar 26,60,93,107,152 but not Sprague-Dawley rats 118. Possibly, these findings suggest there may be strain differences in either post-synaptic 5-HT receptors 17, or non-serotonergic mechanisms (described below) that mediate the behavioral toxicology of MDMA.
Is the Damage Permanent?
In addition, the formation of free radicals after MDMA administration in the mouse striatum was evidenced in our earlier study (Górska et al. 2014). Free radical formation by MDMA was found in the mouse striatum by Colado et al. (2001). The involvement of free radicals in MDMA-induced dopaminergic neurotoxicity in mice was also shown by Peraile et al. (2013). Those authors demonstrated that oxidative stress was related with lipid peroxidation and with an increase in superoxide dismutase and decrease in catalase activity. Hydroxyl radical formation together with products of tryptamine oxidation was proposed as the mechanism of MDMA-induced depletion of brain 5-HT by Shankaran et al. (1999). Moreover, it was suggested that 5-HT depletion was dependent on 5-HT transporter activity.
MDMA and Caffeine Effects on PDYN and PENK Gene Expressions and on Behavior
For an overview of these issues, we refer the reader to an excellent review by Susan Schenk.158 Taken together, MDMA does seem to have reinforcing properties, but these appear to be significantly weaker than those of cocaine. Here, we provide an insight into the synergistic interaction between MDMA and caffeine after the “weekend” mode of drug administration in mice. Our findings indicate that caffeine increased the response of DA neurons to the challenging dose of MDMA while decreasing the response of serotonergic neurons. Caffeine potentiated the oxidative damage of nuclear DNA induced by MDMA and had no effect on MDMA-induced decrease in DAT density in the frontal cortex; however, it reversed MDMA-induced DAT decrease in the striatum. Furthermore, caffeine potentiated the decrease in SERT density produced by MDMA in the frontal cortex. Furthermore, exploratory and locomotor activities of mice decreased by MDMA were not affected by caffeine, but exploration of novel object in the NOR test was diminished in animals treated with MDMA and caffeine.
HUMAN STUDIES
Most of the recent studies and suggestions regarding the targeted treatment for MDMA abuse have focused on attenuating the neurotoxicity and neurotransmitters excitotoxicity in the brain. In future studies, the potential therapeutic substances, either synthetic or natural that can attenuate the long-term effects of MDMA through those involved mechanisms should be highly considered. Many in vivo studies show the close relationship between hyperthermia and neurotoxicity engendered by MDMA .
- As we move forward, let’s approach this topic with open minds, critical thinking, and a commitment to understanding the full spectrum of MDMA’s effects – both good and bad.
- Therefore, a down-regulation of SERT protein expression does not preclude the existence of 5-HT terminal degeneration.
- The involvement of the 5-HT transporter (SERT) in the long-term effects induced by MDMA has been evidenced by many studies.
- Can MDMA cause dependence, and, if so, what treatment approaches are currently available?
Functional consequences of neurotoxic drug regimens
- A locomotor sensitization two weeks after an escalating MDMA regimen was reported 127,128.
- Age-at-first ecstasy use predicted midbrain SERT binding in ecstasy users that started to use during adolescence but not in users that started during adulthood.
- The environment is carefully controlled so that it is aesthetically pleasing and resembles a living space rather than a medical facility.
One from recreation literature and Ecstasy use suggesting potential for neurotoxicity. The other from clinical environments in which MDMA is predominantly therapeutic, has a promising safety profile, and lacks evidence of clinically significant neurotoxicity despite using measures that could reasonably detect such problems. Therefore, models of dosing from clinical trials could be extrapolated and generalized into a harm reduction framework that could be applied broadly to persons who use MDMA.
New object recognition test in mice was carried out using a wooden, black, round “free-field,” placed 80 cm above the floor with a diameter of 100 cm and divided into eight equal sectors with white line. The laboratory room was dark, and only the center of the open field was illuminated with a 25-W bulb placed 75 cm above the platform. On the first day of the experiment (adaptation), mice were placed in the open field for 10 min. On the next day, the animals were placed in the open field for 5 min with two identical objects (white tin, 5 cm wide and 14 cm high or green pyramid 5 cm wide and 14 cm high). Then, 1 h after the first session, the mice were again placed in a free field for 5 min with two different objects, one from the previous session (old) and the other new (white box and green pyramid). The time of object interest was measured for each of the two objects separately (sniffing, touching, or climbing).
The Siren Song of Serotonin
The girl’s brain scan may actually be abnormal, but there is no way to know what caused it (depression can also reduce brain activity, as can fatigue), or if her brain was ever like the “healthy brain” example they showed, or if what changes were seen were merely temporary. Looking back at the first pair of images, you’ll notice two blobs floating on one side of the ‘healthy’ image. The eyes do not appear in the other image, suggesting that different settings have been used–settings that would hide more of the scan’s data. In fact, those two images could possibly have been generated from the same scan of the same person, merely rendered differently. (Antioxidant use is actually good advice for any drug user, including smokers and drinkers.) Visit Preloading for more information on antioxidants.
Neurochemical and Neurotoxic Effects of MDMA (Ecstasy) and Caffeine After Chronic Combined Administration in Mice
Our findings confirm previous animal findings that MDMA affects the developing brain differently and extend these observations for the first time to humans. These age-related effects most likely reflect the maturational stage of the 5-HT projection fields at age-at-first exposure and enhanced outgrowth of the 5-HT system due to 5-HT’s neurotrophic effects. At what age the 5-HT system becomes fully sensitive the MDMA’s neurotoxic effects is dependent on the developmental status of SERT and the maturation of 5-HT’s neurotransmitter function. These findings support the notion that during brain development the degree of structural plasticity of ascending 5-HT projections is higher than at later stages. To what extent these findings can be extrapolated to other drugs of abuse and medicines that have their primary action on the 5-HT system, is difficult to predict. Ultimately our data illustrate the need for more knowledge on the effects of pharmacotherapies that increase 5-HT levels during brain development, such as SSRIs for the treatment of childhood depression and anxiety disorders.
Treatment of rats with 5-HT precursors, tryptophan or 5-hydroxytryptophan, was shown to attenuate MDMA-induced serotonergic deficits as measured by 3H-paroxetine binding and 5-HT content in the striatum, hippocampus, and frontal cortex of the rat brain 176. These authors suggested that 5-HT depleted terminals are more vulnerable to the toxic effects of MDMA, and so, 5-HT precursors would protect 5-HT terminals by replenishing the vesicular stores. It should also be noted, however, that rats depleted of vesicular and cytoplasmic dopamine mdma and the brain: is ecstasy neurotoxic stores by means of previous treatment with reserpine and α-methyl-p-tyrosine (AMPT) showed no deficits of 5-HT after MDMA. Importantly, these animals did not turned hyperthermic but hypothermic and when this effect was averted by raising ambient temperature, the 5-HT neuroprotective effects of reserpine and AMPT were no longer apparent, suggesting that dopamine per se is not essential for the expression of MDMA-induced 5-HT neurotoxicity 125.
People also often use it alongside alcohol or other drugs, which may enhance the negative effects. Despite these superficial similarities, their chemical structures, primary mechanisms of action, and specific dangers are distinct. MDMA’s primary impact on serotonin and its empathogenic effects set it apart from methamphetamine’s potent, primarily dopaminergic stimulation. Methamphetamine carries a much higher addiction liability and more severe long-term physical and psychological consequences. SPECT studies were acquired in all subjects with a brain dedicated SPECT system (Strichman Medical Equipment 810X, Strichman Medical Equipment Inc., Medfield, Mass., USA).