Therapeutic effects of mdmA

1. Therapeutic effects of mdmA • Annie Chen • Cynthia Le • Daniel Hagan • Mustafa Nasr (3,4-Methylenedioxymethamphetamine)

2. Table of Contents • Mechanism of Action • Therapeutic Neurobiological Mechanism • Neurotoxicity • Long term Serotonergic Changes • Structural Changes in Serotonergic Axons • Role of Oxidative Stress in Neurotoxicity • Safety Assessment in Clinical Studies • Therapeutic Potential • Therapeutic Benefits • Therapeutic Dangers • History of Therapeutic Use of MDMA • Role of Mental Set • Results and Conclusion • Therapeutic Use of MDMA Today • MDMA-PTSD U.S. Pilot Study

4. Mechanism of Action • Primarily serotonergic, but also effects norepinephrine and dopamine • Enters pre-synaptic cell via monoamine transporters • Inhibits vesicular monoamine transporter • Releases monoamines by reversal of respective transporters through phosphorylation • Also acts as a weak 5-HT, and 5-HT2 agonist • Causes indirect oxytocin secretion by stimulating serotonin system • Inhibits rate-limiting enzyme for 5-HT synthesis; typtophan hydroxylase

5. MDMA (Ecstasy) • MDMA in synaptic cleft

6. Therapeutic Neurobiological Mechanism • Increased oxytocin levels strengthen alliance between patients and therapist • Decrease in amygdala activity with an increase in ventromedial prefrontal activity improves emotional regulation and decreases fear and avoidance • Increase in norepinephrine and cortisol levels facilitates emotional engagement and extinction of learned fear associations

7. Neurotoxicity • Appears to have same risk for neurotoxicity as other psycho-stimulants (i.e. methamphetamine) • Very modest risk of acute toxicity in controlled environment • Studies with animals have shown that MDMA can decrease brain-functions that rely on serotonin on a long-term basis ( >7 days) • However, it is unclear what effect this has on the animals • No studies have investigated whether MDMA causes neurotoxicity that only becomes apparent with aging

8. Longterm Serotonergic Changes • Decreased brain concentrations of serotonin and its metabolite 5-HIAA • Decrease in density of SERT (serotonin re-uptake transporter) • Is this down-regulation? Or have serotonergic axons been permanently lost or damaged? • Down regulation suggests an active adaptation to the increase in serotonin from ecstasy (MDMA) while axonal loss suggests true damage

10. Structural Changes to Serotonergic Axons • Looking at the structure of serotonergic axons in animals exposed to MDMA clearly indicates axonal loss • Slices of MDMA exposed animal brain tissue in which 5-HT has been stained show irregular swelling and fragmentation of fine serotonergic axons • Swelling suggest damage of axons and this can be proven by measuring the movement of compounds between brain regions connected by serotonergic axons

11. Role of Oxidative Stress in Neurotoxicity • Highly reactive chemicals call free radicals damage neural molecules through reduction and oxidation. These reactions alter the ability of neural cells to carry out their normal functions • MDMA has been shown to increase oxidative stress in the brain by two separate methods • Antioxidants are molecules that react with free-radicals to create harmless molecules

12. Role of Oxidative Stress in Neurotoxicity cont... • Mice given extreme doses of antioxidants (or genetically altered to have naturally elevated levels of antioxidants) such as vitamin C and alpha-lipoic acid show no signs of neurotoxicity when given a normally neurotoxic regiment of MDMA (the dose of MDMA and vitamin C are very high) • Sustained effects of MDMA may deplete neuronal energy sources and their ability to deal with oxidative stress • Both MDMA and Dopamine can be metabolized into highly reactive molecules

13. Safety Assessment in Clinical Studies • Range of psychoactive, but non-neurotoxic MDMA closes appears small in most animals • However, the dosage and frequency of administration can be kept to the minimum required • Furthermore, methods for reducing or blocking neurotoxicity in animals can be employed and likely reduce neurotoxicity at least to some degree in humans

14. Safety Assessment in Clinical Studies cont... • Methamphetamine has shown to exhibit at least the same neurotoxicity as MDMA, but the FDA still approves of methamphetamine • SSRI’s block SERT and inhibits the function of MDMA • When given 3-4 hours after a neurotoxic regiment of MDMA, several SSRI’s (such as paroxotine, fluoxetine and citalopram) can block neurotoxicity in rodents. Although human-trials have not been conducted it is likely that they have a similar effect in humans.

15. Therapeutic Potential • Physical and Psychological distress of terminal cancer patients • Treatment of PTSD (post-traumatic stress disorder) caused by: • Sexual assault • War • Violent crimes

16. Therapeutic Benefits • Helps break down boundaries in communication • Especially useful for patients who are aggressive, defensive and unwilling to “open up” • Increased feelings of empathy • Increased feelings of acceptance • Depersonalization; loosening of ego and boundaries • Feelings of tranquility and peace

17. Therapeutic Dangers • Chance of psychological dependence • Possible adverse effects • increased body temp • increased heart rate and blood pressure • muscle tension • jaw clenching nausea • Impairment of episodic and working memories and attention

18. History of Therapeutic Use of MDMA • Greer & Tolbert • MDMA assisted • psychotherapy sessions from • 1980 to 1985 • 80 patients total • screening criteria and informed consent • mental set and psychological preparation emphasized

19. Role of Mental Set • Set includes expectations, motivations and intentions of individual in regard to the session • Mental set both patient and therapist important • Goal of developing more compassionate attitude was easily achieved by MDMA-assisted therapy • Relief from chronic symptoms and behavior problems greater when such change in attitude occurred • Approached sessions more as sacred rites of passage than conventional therapy sessions

20. Results & Conclusions • MDMA seems to decrease fear response to perceived threat to patient’s emotional integrity • Leads to corrective emotional experience • Diminishes pathological effects of previous traumatic experiences • Acquisition of effective skills for communicating feelings to family members • Psychological benefits were lasting up to a 2-year follow-up for most patients

21. Therapeutic Use of MDMA Today • Currently only one FDA & DEA approved medical study on MDMA (Schedule 1 drug) • MAPS (multidisciplinary association of psychedelic studies) is studying whether MDMA-assisted psychotherapy has potential to heal traumas caused by sexual assault, war, violent crime and other causes • In the middle of a 10 year, $10 million plan to make MDMA a government-approved prescription medication

22. MDMA-PTSD U.S. Pilot Study • 1st ever protocol evaluating MDMA’s therapeutic applications in clinical trials • Randomized, double blind and placebo controlled • 21 subjects with treatment resistant PTSD • MDMA-assisted psychotherapy produced statistically significant improvements in PTSD symptoms • Difference between 2 groups was immediate and maintained throughout the time period

23. Sources • http://www.maps.org/research/mdma/ • http://www.macalester.edu/psychology/whathap/ubnrp/mdma/therapeutic.html • http://www.lycaeum.org/research/researchpdfs/1998_greer_1.pdf • Peroutka, Stephen J. Ecstasy: the Clinical, Pharmacological, and Neurotoxicological Effects of the Drug MDMA. Boston: Kluwer Academic, 1990. • http://www.science.smith.edu/departments/Biochem/Chm_357/Articles/ecstasy%20toxicity.pdf • http://www.erowid.org/library/books/ecstasy_complete.shtml • http://www.idmu.co.uk/ecstasy-information/ • http://www.springerlink.com/content/9rvc16g5hgmdg6wb/