Therapeutic effects of Therapeutic effects of mdmAmdmA

Annie ChenCynthia Le

Daniel HaganMustafa Nasr

(3,4-Methylenedioxymethamphetamine)

Table of ContentsTable of ContentsMechanism 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

Mechanism of ActionMechanism 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

MDMA (Ecstasy)MDMA (Ecstasy)MDMA in synaptic cleft

Therapeutic Therapeutic Neurobiological Neurobiological

MechanismMechanismIncreased 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

NeurotoxicityNeurotoxicityAppears 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

Longterm Serotonergic Longterm Serotonergic ChangesChanges

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

Structural Changes to Structural Changes to Serotonergic AxonsSerotonergic 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

Role of Oxidative Role of Oxidative Stress in NeurotoxicityStress 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

Role of Oxidative Role of Oxidative Stress in Neurotoxicity Stress in Neurotoxicity

cont...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

Safety Assessment in Safety Assessment in Clinical StudiesClinical 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

Safety Assessment in Safety Assessment in Clinical Studies cont...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.

Therapeutic PotentialTherapeutic Potential

Physical and Psychological distress of terminal cancer patients

Treatment of PTSD (post-traumatic stress disorder) caused by:

Sexual assault

War

Violent crimes

TherapeutTherapeutic ic

BenefitsBenefitsHelps 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

TherapeutiTherapeutic Dangersc 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

History of History of Therapeutic Therapeutic

Use of MDMAUse of MDMAGreer & Tolbert

‣MDMA assisted

‣psychotherapy sessions from

‣1980 to 1985

‣80 patients total

‣screening criteria and informed consent

‣mental set and psychological preparation emphasized

Role of Role of Mental SetMental 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

Results & Results & ConclusionConclusion

ssMDMA 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

Therapeutic Use of Therapeutic Use of MDMA TodayMDMA 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

MDMA-PTSD U.S. Pilot MDMA-PTSD U.S. Pilot StudyStudy

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

SourcesSourceshttp://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/