The Brain Damage of MDMA ("Ecstasy")

[Bucklecroft Rudy]

The subject of this article is the brain damage, or neurotoxicity, caused by the psychoactive drug 3,4-methylenedioxy-N-methylamphetamine (MDMA; "Ecstasy" ("E", "X", "XTC"), "Adam", "Empathy", "Molly", etc), and how to effectively prevent it with neuroprotective substances. It is written in a simple and easy to understand manner and is directed toward the average recreational user of MDMA. For the more curious or technically-oriented readers, an advanced approach may also be found here:

An Analysis of MDMA-induced Neurotoxicity

To understand the neurotoxicity caused by MDMA, some basic concepts must be covered first. Serotonin is a neurotransmitter, or chemical that mediates communication between brain cells, or neurons, in the nervous system. Neurons that respond to this chemical are said to be serotonergic. MDMA primarily induces a massive release of serotonin to cause its psychological and physiological effects. However, detrimentally to its use, MDMA has also been demonstrated to be selectively neurotoxic to serotonergic neurons in various scientific studies. Importantly, it has been shown that MDMA itself does not actually cause the neurotoxicity, and that other compounds that MDMA is converted into once it is inside the body, or its metabolites, are the true mediators of the damage.

Neurons are protected by a protective barrier known as a plasma membrane which separates the cell from the outside world and keeps foreign substances out. Due to the plasma membrane, MDMA must use a specialized structure called the serotonin transporter (SERT) to get into serotonergic neurons. The SERT responds to and carries compounds like serotonin and MDMA, among others, from the outside into the cell. Once inside the cell, MDMA induces serotonin release to exert its effects. Notably, the toxic metabolites of MDMA also use the SERT to get into the cell and upon doing so, they damage it from the inside. For that reason, serotonin transporter blockers, also known as serotonin reuptake inhibitors (SRIs), can fully block the damage induced by MDMA. However, they will also block MDMA's effects if taken at the same time. This can be avoided by taking the SRI exactly three hours after dosing MDMA. No actual damage occurs until MDMA's effects wear off, so this will still ensure proper protection against the neurotoxicity.

The reason no damage occurs until MDMA's effects wear off is a matter of competition. Molecules can only be transported by the SERT one at a time. Therefore, they must compete with other compounds such as serotonin and MDMA for entry into the cell. With MDMA present in high concentrations and serotonin floating around in massive quantities, the toxic metabolites have literally no chance of getting transported into the cell in amounts sufficient enough to cause significant damage. That is, however, until MDMA's effects wear off after 3-4 hours. By that point in time, MDMA has been largely cleared from the body and serotonin levels are also much lower than usual due to acute tolerance (also sometimes referred to as a "hangover"). The result of this is far less competition and activity going on at SERT. The toxic metabolites then don't have to compete for access into the cell nearly as much and they can therefore get into it relatively easily. Once they're inside, heavy damage ensues. The reason serotonin precursors like L-tryptophan and 5-hydroxytryptophan (5-HTP) are neuroprotective, is because they increase serotonin levels after the roll, giving the toxic metabolites more competition, and making it harder for them to get into the cell.

The toxic metabolites of MDMA cause their damage by a process known as oxidative stress. Oxidative stress is caused by the generation of reactive oxygen species, or free radicals, highly reactive particles that rip apart other molecules and induce chain reactions of destruction. It appears that MDMA's metabolites are further metabolized from within the cell by at least two enzymes, or structures that mediate chemical reactions, monoamine oxidase B (MAO-B) and cyclooxygenase (COX). It is believed that the toxic free radicals are generated as byproducts of the metabolic conversions. For that reason, MAO-B inhibitors and COX inhibitors, which disable MAO-B and COX enzymes from working, respectively, also block the damage caused by MDMA. Additionally, antioxidants, or compounds that scavenge and destroy free radicals, block the damage as well; though, they likely do not do so nearly as effectively as MAO-B and COX inhibitors, which prevent the free radicals from ever even being generated in the first place.

If at least two major neuroprotective strategies are employed, e.g., an MAO-B or COX inhibitor before, and an SRI after the roll, full protection is very likely to be warranted.

List of recommended substances neuroprotective against MDMA-induced neurotoxicity:

Antioxidants:
Acetyl-L-Carnitine
Alpha Lipoic Acid
Ascorbic Acid (Vitamin C)
Carotenoids/Retinoids (Vitamin A)
Flavonoids (found in Camellia Sinensis ("Green Tea"), Ginkgo Biloba ("Ginkgo"), etc.)
Melatonin
N-Acetylcysteine
Selenium
Tocopherols/Tocotrienols (Vitamin E)
Ubiquinone (Coenzyme Q)
Cyclooxygenase (COX) Inhibitors:
Aspirin (Bayer)
Ibuprofen (Advil, Motrin)
Naproxen (Aleve)
Monoamine Oxidase B (MAO-B) Inhibitors (MAOIs):
Pargyline (Eutonyl)
Rasagiline (Azilect)
Selegiline (Eldepryl, Zelapar, Emsam)
Serotonin Reuptake Inhibitors (SRIs):
Selective Serotonin Reuptake Inhibitors (SSRIs):
Citalopram (Celexa)
Dapoxetine (Priligy)
Escitalopram (Lexapro, Cipralex)
Fluoxetine (Prozac)
Fluvoxamine (Luvox)
Paroxetine (Paxil, Seroxat)
Sertraline (Zoloft, Lustral)
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs):
Desvenlafaxine (Pristiq)
Duloxetine (Cymbalta)
Milnacipran (Ixel, Savella)
Venlafaxine (Effexor)
Tricyclic Antidepressants (TCAs):
Amitriptyline (Elavil)
Clomipramine (Anafranil)
Dosulepin/Dothiepin (Prothiade)
Doxepin (Adapin, Sinequan)
Imipramine (Tofranil)
Lofepramine (Gamanil, Lomont)
Trimipramine (Surmontil)
Others:
Chlorpheniramine (Chlor-Trimeton)
Sibutramine (Meridia, Reductil)
Tramadol (Tramal, Ultram)
Serotonin Synthesis Precursors:
5-Hydroxytryptophan (5-HTP)
L-Tryptophan

Warning: Do not take a nonselective MAOI such as phenelzine (Nardil), tranylcypromine (Parnate), or isocarboxazid (Marplan), or a selective MAO-A inhibitor such as moclobemide (Aurorix, Manerix), with MDMA under any circumstance, as it can potentially dangerously elevate serotonin levels to the point of serotonin syndrome, and may very well prove to be fatal. It should also be noted that doses of selegiline above 15 mg may become nonselective as well.
NAME WITHELD
(email: <snip>
June 6th, 2009 (last updated June 11th)

 

[happyland]

taking a COX inhibitor such as Naproxen (Aleve) serveral hours after consuming MDMA is safe? thinking of giving it a try tomorrow night. also will be taking vit a,c,e along with R-Lipoic Acid. shouldnt be any trouble right?

edit:
would the inhibition of COX just delay/prolong the the rate which mdma is metabolized? leading to a longer than normal period of free radicals present? sorry if question dosent make sense.. about to pass out

 

[Bucklecroft Rudy]

taking a COX inhibitor such as Naproxen (Aleve) serveral hours after consuming MDMA is safe? thinking of giving it a try tomorrow night. also will be taking vit a,c,e along with R-Lipoic Acid. shouldnt be any trouble right?

edit:
would the inhibition of COX just delay/prolong the the rate which mdma is metabolized? leading to a longer than normal period of free radicals present? sorry if question dosent make sense.. about to pass out

An Analysis of MDMA-induced Neurotoxicity

NAME WITHELD
(email: <snip>
April 16, 2009 (last updated May 17th)

Introduction

3,4-methylenedioxy-N-methylamphetamine (MDMA, "Ecstasy", "Adam", "E", "X", "XTC") is a psychoactive drug of widespread recreational use and scientific as well as clinical interest. Its effects have been described as a cross between a stimulant and a mild psychedelic. Unlike the other drugs of these two respective classes, however, MDMA is particularly intriguing for its unique entactogenic properties, of which include the following:

A strong sense of inner peace and self-acceptance.
Diminished aggression, hostility, and jealousy.
Diminished fear, anxiety, and insecurity.
Extreme mood-lift with accompanying euphoria.
Feelings of empathy, compassion, and forgiveness towards others.
Feelings of intimacy and even love for others.
Feelings of insightfulness and mental clarity.
Improved self-confidence without the incidence of arrogance.
The ability to discuss normally anxiety-provoking topics with marked ease.

Such qualities have proven MDMA to be highly useful in assisting psychotherapy, as well as perhaps in the treatment of disorders of a social nature, such as excessive anxiety or anger. Indeed, it was used for many years in therapy and was hailed as the greatest tool psychiatry had ever seen for such purposes. Some claimed that a single MDMA-assisted therapy session could accomplish as much as six months or more of standard therapy. Although MDMA is now a controlled substance in most parts of the world, it is still used underground by many psychiatrists and is also being investigated for the clinical treatment of post-traumatic stress disorder, as an adjunct to therapy. It has also been suggested as a novel treatment for depression with a rapid onset of action and far greater efficacy than current antidepressants. Some have even gone as far as proposing that MDMA could be utilized as a kind of utopian drug of sorts. Undoubtedly, it does seem to imbue a person with a bill of perfect mental health for the duration of its effects.

Unfortunately, MDMA has been shown to be toxic to serotonin neurons in the brains of rodents and monkeys, and is very likely to be toxic to humans as well. As expected, this toxicity significantly impairs MDMA's potential clinical usefulness and puts recreational users at a high risk for developing severe and long-term brain damage. The purpose of this review is to analyze the mechanisms behind MDMA-induced neurotoxicity (MIN) and to find effective ways of preventing it, while at the same time not significantly altering the psychological and physiological effects of the MDMA experience.

Pharmacology of MDMA

In order to understand MIN, it is first necessary to recognize the manner in which MDMA exerts its effects. MDMA is a release agent and reuptake inhibitor of the monoamine neurotransmitters serotonin (5-HT), norepinephrine (NE), and dopamine (DA). Its action is strongest on 5-HT and its dissociation constants for 5-HT, NE, and DA release are 74.3, 136, and 278 (less is more), respectively. It works by individually binding to and being carried into the pre-synaptic neuron by the respective serotonin (SERT), norepinephrine (NET), and dopamine transporters (DAT). Once inside the cell, MDMA does two things. It binds to and inhibits the vesicular monoamine transporter type 2 (VMAT2), thereby preventing intracellular neurotransmitters from being repackaged into vesicles, and induces phosphorylation of the monoamine transporters, resulting in a reversal of their action. This causes 5-HT, NE, and DA all to be dumped into the synapse. The released neurotransmitters then bind to receptors located on the post-synaptic neuron, ultimately resulting in an increase in neurotransmission.

In translation, the increase in 5-HT appears to mediate the entactogenesis and psychedelia, while NE and DA contribute stimulation. A synergy between 5-HT and DA appears to be the cause of the mood lift and anxiolysis. It is interesting to note that more DA is ultimately released than either 5-HT or NE, despite MDMA having a higher efficacy for directly releasing both 5-HT and NE. This is likely due to 5-HT and NE's ability modulate the DA system in certain parts of the brain.

It is also important to cover MDMA's metabolism. MDMA is degraded by a number of enzymes, including the cytochrome P450s (CYPD450) 1A2 (CYP1A2), 2B6 (CYP2B6), 2D6 (CYP2D6), and 3A4 (CYP3A4), as well as by catechol O-methyltransferase (COMT), and monoamine oxidase (MAO). Its primary metabolites include 3,4-methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxy-N-methylamphetamine (HMMA), and 4-hydroxy-3-methoxyamphetamine (HMA). Other metabolites that occur to a lesser extent include 3-hydroxy-4-methoxyamphetamine, 3,4-dihydroxyamphetamine (alpha-methyldopamine), 3,4-dihydroxy-N-methylamphetamine (N-methyl-alpha-methyldopamine), 3,4-methylenedioxyphenylacetone, 3-4-dihydroxyphenylacetone, and 4-hydroxy-3-methoxyphenylacetone.

Neuroprotective Agents

It has been demonstrated in various studies that a number of different classes of compounds are capable of blocking or reducing MIN. Such substances include serotonin reuptake inhibitors (SRIs) [1-2], antioxidants [3-5], inhibitors of the enzyme monoamine oxidase type B (MAO-B) [6-7], and inhibitors of the enzyme cyclooxygenase (COX), also known less commonly as prostaglandin H synthase (PHS). It has also been shown that the direct injection of MDMA into the brain does not result in MIN [8-9]. Seeing as how intracranial injection is a generally completely impractical method of administration, the fact that MDMA injected directly into the brain does not cause MIN is only really useful as a scientific observation, which will be demonstrated below.

Notably, SRIs also largely block the release of 5-HT induced by MDMA, leading to a substantial reduction in its effects, as well as MIN. This is because SRIs inhibit the function of the SERT, which carries substrates like 5-HT and MDMA into the pre-synaptic cell. Carriage by the SERT into the cell is necessary for MDMA to induce the release of 5-HT, as it causes this via an intracellular mechanism. With the SERT blocked by a SRI, the action of MDMA as a 5-HT releaser is subsequently blocked as well. Therefore, SRIs are also generally unreliable as a way of getting around MIN.

Mechanism of Toxicity

Because antioxidants block MIN and because free radical generation induced by MDMA has been observed in scientific studies, it can be concluded that oxidative stress is the mediator behind MIN [10-12]. Oxidative stress is caused by the formation of free radicals, highly reactive oxygen species containing unpaired electrons which rip apart other molecules and induce chain reactions of destruction. Therefore, MDMA or one or more of its metabolites induces the generation of free radicals, likely as byproducts of an enzymatic reaction. Since MDMA injected directly into the brain does not result in MIN, it can be further concluded that MDMA itself is not toxic, one or more of MDMA's metabolites are the true cause of the toxicity, and the formation of the metabolites occurs solely in the periphery. This view is also supported by the fact that MAO-B and COX inhibitors, which prevent certain metabolic pathways of MDMA and/or its metabolites, are also protective against the damage.

Role of Metabolism

Both MAO-B and COX enzymes exist widely throughout both the periphery and the brain. MDMA injected directly into the brain does not result in MIN, however. This would mean that MAO-B and COX enzymes do not degrade MDMA into toxic metabolites. Yet both MAO-B and COX inhibitors are protective against MIN. This is a bit of a paradox, but there is a simple and logical possible explanation for it. The toxic metabolites of MDMA are first formed in the periphery, possibly by the CYPD450s. Once formed, these toxic metabolites then make it into the brain, where they are further metabolized by MAO-B and/or COX, ultimately spawning free radicals in the process.

In order for the toxic metabolites of MDMA to properly find their way into 5-HT neurons, they themselves must have affinity for the SERT. The affinity must also be selective, as MDMA is specifically toxic only to 5-HT neurons, and not to NE or DA cells. Finally, they must be substrates for the MAO-B and/or COX enzymes found within the pre-synaptic cell.

There are already several candidates for such a metabolite. They include alpha-methyldopamine and N-Methyl-alpha-methyldopamine, as well as 2,5-bis(glutathion-S-yl)-alpha-methyldopamine, all of which have been shown to be metabolites of MDMA [13]. Others which have not yet been demonstrated to be metabolites of MDMA, but may play a role in MIN, include 5-(glutathion-S-yl)-alpha-methyldopamine, and 5-(N-acetylcystein-S-yl)-alpha-methyldopamine [14]. It has been shown that 2,5-bis(glutathion-S-yl)-alpha-methyldopamine injected directly into the brain causes neurotoxicity virtually indistinguishable from MIN [15]. Additionally, many of these metabolites demonstrated affinity for the SERT, NET, and/or DAT, and induce the release of 5-HT, NE, and/or DA similarly to MDMA [16]. Whether 2,5-bis(glutathion-S-yl)-alpha-methyldopamine is solely responsible for MIN, or if other metabolites are also involved, is still a matter of debate.

Role of Dopamine

Consistent with their similar chemical structure, both MDMA and DA have been shown to reduce to toxic metabolites, which exert their damage via oxidative stress. As a result, it has been suggested that DA may significantly, or possibly even primarily contribute to MIN [17]. DA's immediate metabolite, 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is formed by the reaction of DA with MAO-B, is toxic to DA cells. In fact, DOPAL is believed to be the main culprit behind the progressive neurodegeneration seen in patients with Parkinson's disease. Similarly to MDMA, it has been demonstrated in various studies that the pre-adiministration of a MAO-B or COX inhibitor with DOPAL reduces the toxicity to exposed tissues.

The idea regarding DA playing a role in MIN is as follows. Dopamine itself has low binding affinity to SERT. It is thought that MDMA temporarily depletes 5-HT stores to such an extent, that DA does not need to compete as much with 5-HT for SERT binding and carriage. As a result, DA can easily get into 5-HT neurons in large amounts, something that would not happen normally to a significant extent. Once inside the cell, DA is reduced by MAO-B and/or COX, ultimately spawning free radicals somewhere down the metabolic line.

This theory appears to be flawed for several reasons. Firstly, MDMA has been shown to be selectively toxic only to 5-HT neurons and not to DA neurons, at least in rats. This is contradictory because logically DA neurons should be damaged as well, and to an even greater extent than 5-HT cells, yet they are not. Secondly, MDMA injected directly into the brain does not result in MIN. This could potentially be explained by MDMA itself perhaps being inactive as a DA releaser, and a metabolite formed in the periphery being the true releaser of DA, however. Whether this is the case or not is currently unknown. Thirdly, it has been demonstrated that a combination of reserpine and alpha-methyl-para-tyrosine administered prior to MDMA does not block MIN, despite a near full depletion of DA stores [18-19]. Fourthly and finally, aminorex and 4-methylaminorex, distantly related homologues of amphetamine which induce the simultaneous release of 5-HT and DA almost equipotently, have been demonstrated to be either insignificantly toxic or only very mildly toxic. It is likely that in relation to their distant chemical structure to and unlike the amphetamines, the aminorexes do not reduce to toxic metabolites. Their nearly negligible toxicity is consistent with the idea that the induced release of DA plays only a very minor role in MIN.

There are still two main arguments for a major role of DA in MIN, however. Firstly, there appears to be a strong correlation between MIN and combined 5-HT and DA release among various amphetamine analogues. Secondly, it has been demonstrated that the combination of a non-toxic and selective 5-HT releaser with amphetamine, a DA and NE releaser which also releases 5-HT to a much lesser extent, results in subsequent 5-HT toxicity. The latter argument may be flawed, however, because amphetamine itself is mildly toxic to both 5-HT and DA neurons. The toxicity may have simply been exacerbated by the hyperthermia induced by 5-HT (see below). Furthermore, in regards to the first argument, perhaps simultaneous 5-HT and DA release only aggravates MIN by increased levels of DA contributing to 5-HT-induced hyperthermia via stimulation of the D1 receptors (also see below) [20].

Further studies must be conducted to properly determine whether DA truly plays a major role in MIN. One idea would be to combine a non-toxic and selective 5-HT releaser with a non-toxic and selective dopamine reuptake inhibitor (DRI), such as amfonelic acid, and see if toxicity ensues. Another would be to see if MDMA injected directly into the brain results in both 5-HT and DA release.

Role of Hyperthermia

One of MDMA's effects is the induction of hyperthermia, mainly through action on the 5-HT system. It has been demonstrated that the higher the ambient body temperature, the worse the MIN [21-22]. A possible explanation for this is the higher the temperature, the greater the probability that enzymes such as MAO-B and COX will catalyze chemical reactions and therefore generate free radicals. A number of agents have been shown to reduce MIN by inhibiting MDMA-induced hyperthermia, including 5-HT1A, 5-HT2, D1, and NMDA receptor antagonists, as well as GABA-B receptor agonists. Despite inhibiting MIN to some extent, it is likely that these agents do not prevent the bulk of the damage, however.

Future Prospects

The ultimate goal will not be to prevent MIN with additional drugs, but to develop analogues of MDMA that actually lack the toxicity themselves. An ideal drug would not metabolize in such a way that would cause oxidative stress, and would be perfectly safe to indulge in, whether it be a single time or a hundred times. The role of such a drug has actually already been fulfilled to an extent. The aminoindan homologues of MDMA, 5,6-methylenedioxy-2-aminoindan (MDAI) and 5-methoxy-6-methyl-2-aminoindan (MMAI), developed by David E. Nichols at Purdue University, are fully non-toxic MDMA-like compounds [23-24]. Despite the fact that they substitute for MDMA in rat drug discrimination tests, they are selective only for 5-HT, and do not induce the release of NE or DA. This is somewhat unfortunate, as it is likely that they will be much less euphoric and reinforcing than MDMA itself. Further developments must be undertaken for a truly worthy non-toxic MDMA replacement to emerge.

Conclusion

To summarize, MIN is the result of oxidative stress caused by the formation of free radicals via the reduction of a metabolite of MDMA by the enzymes MAO-B and/or COX. Additionally, the simultaneous release of 5-HT and DA may also play a role via the reduction of DA by MAO-B and/or COX into toxic free radical-generating metabolites from within 5-HT neurons, though there is some evidence against this. Finally, hyperthermia plays a contributing role possibly by increasing the efficiency of the enzymes that degrade MDMA and/or DA into toxic metabolites.

Agents that may be capable of completely and directly blocking MIN without altering the psychological and physiological effects of MDMA, include antioxidants, MAO-B inhibitors, and COX inhibitors. SRIs both substantially reduce the effects of MDMA and fully block MIN. Agents that inhibit MIN to some extent by diminishing the contributing hyperthermia, include 5-HT1A, 5-HT2, D1, and NMDA receptor antagonists, as well as GABA-B receptor agonists. If DA truly does play a major role in MIN, DRIs, like SRIs, would be capable of blocking the MDMA-induced release of DA, and therefore most of the DA-mediated neurotoxicity as well. However, this would not resolve all of MIN and would also result in a partial reduction in MDMA's effects.

There is much data on the subject of MIN, but we are still a ways away from fully understanding it. Hopefully in the future more studies will be conducted, shedding further light on this complex subject. It is important that this occurs as to help educate and protect the millions of recreational MDMA users worldwide from as much harm as possible, and to make the potential clinical use of MDMA a more practical concept.

References

1). Virden TB, Baker LE. (1999) Disruption of the discriminative stimulus effects of S(+)-3,4-methylenedioxymethamphetamine (MDMA) by (+/-)-MDMA neurotoxicity: protection by fluoxetine. Behav Pharmacol. 10(2), 195-204.
2). Farré M, Abanades S, Roset PN, Peiró AM, Torrens M, O'Mathúna B, Segura M, de la Torre R. (2007) Pharmacological interaction between 3,4-methylenedioxymethamphetamine (ecstasy) and paroxetine: pharmacological effects and pharmacokinetics. J Pharmacol Exp Ther. 323(3), 954-962.
3). Shankaran M, Yamamoto BK, Gudelsky GA. (2001) Ascorbic acid prevents 3,4-methylenedioxymethamphetamine (MDMA)-induced hydroxyl radical formation and the behavioral and neurochemical consequences of the depletion of brain 5-HT. Synapse. 40(1), 55-64.
4). Alves E, Binienda Z, Carvalho F, Alves CJ, Fernandes E, de Lourdes Bastos M, Tavares MA, Summavielle T. (2009) Acetyl-L-carnitine provides effective in vivo neuroprotection over 3,4-methylenedioximethamphetamine-induced mitochondrial neurotoxicity in the adolescent rat brain. Neuroscience. 158(2), 514-523.
5). Aguirre N, Barrionuevo M, Ramírez MJ, Del Río J, Lasheras B. (1999) Alpha-lipoic acid prevents 3,4-methylenedioxy-methamphetamine (MDMA)-induced neurotoxicity. Neuroreport. 10(17), 3675-3680.
6). Sprague JE, Nichols DE. (1995) The monoamine oxidase-B inhibitor L-deprenyl protects against 3,4-methylenedioxymethamphetamine-induced lipid peroxidation and long-term serotonergic deficits. J Pharmacol Exp Ther. 273(2), 667-673.
7). Alves E, Summavielle T, Alves CJ, Gomes-da-Silva J, Barata JC, Fernandes E, Bastos Mde L, Tavares MA, Carvalho F. (2007) Monoamine oxidase-B mediates ecstasy-induced neurotoxic effects to adolescent rat brain mitochondria. J Neurosci. 27(38), 10,203-10,210.
8). Esteban B, O'Shea E, Camarero J, Sanchez V, Green AR, Colado MI. (2001) 3,4-Methylenedioxymethamphetamine induces monoamine release, but not toxicity, when administered centrally at a concentration occurring following a peripherally injected neurotoxic dose. Psychopharmacology (Berl). 154(3), 251-260.
9). Escobedo I, O'Shea E, Orio L, Sanchez V, Segura M, de la Torre R, Farre M, Green AR, Colado MI. (2005) A comparative study on the acute and long-term effects of MDMA and 3,4-dihydroxymethamphetamine (HHMA) on brain monoamine levels after i.p. or striatal administration in mice. Br J Pharmacol. 144(2), 231-241.
10). Cadet JL, Thiriet N, Jayanthi S. (2001) Involvement of free radicals in MDMA-induced neurotoxicity in mice. Ann Med Interne (Paris). 152 Suppl 3, IS57-9.
11). Li SX, Sun AM, Wang X, Li J, Peng ZG, Kuang WH, Huang MS. (2006) A preliminary study on the mechanism of neurotoxicity of MDMA - oxidative stress harm. Sichuan Da Xue Xue Bao Yi Xue Ban. 37(2), 191-195.
12). Zhou JF, Chen P, Zhou YH, Zhang L, Chen HH. (2003) 3,4-Methylenedioxymethamphetamine (MDMA) abuse may cause oxidative stress and potential free radical damage. Free Radic Res. 37(5), 491-497.
13). Shenouda SK, Varner KJ, Carvalho F, Lucchesi PA. (2009) Metabolites of MDMA induce oxidative stress and contractile dysfunction in adult rat left ventricular myocytes. Cardiovasc Toxicol. 9(1), 30-38.
14). Bai F, Lau SS, Monks TJ. (1999) Glutathione and N-acetylcysteine conjugates of alpha-methyldopamine produce serotonergic neurotoxicity: possible role in methylenedioxyamphetamine-mediated neurotoxicity. Chem Res Toxicol. 12(12), 1150-1157.
15). Miller RT, Lau SS, Monks TJ. (1997) 2,5-Bis-(glutathion-S-yl)-alpha-methyldopamine, a putative metabolite of (+/-)-3,4-methylenedioxyamphetamine, decreases brain serotonin concentrations. Eur J Pharmacol. 323(2-3), 173-80.
16). Monks TJ, Jones DC, Bai F, Lau SS. (2004) The role of metabolism in 3,4-(')-methylenedioxyamphetamine and 3,4-(')-methylenedioxymethamphetamine (ecstasy) toxicity. Ther Drug Monit. 26(2), 132-136.
17) Sprague JE, Nichols DE. (2005) Neurotoxicity of MDMA (ecstasy): beyond metabolism. Trends Pharmacol Sci. 26(2), 59-60; author reply 60-61.
18. Yuan J, Cord BJ, McCann UD, Callahan BT, Ricaurte GA. (2002) Effect of depleting vesicular and cytoplasmic dopamine on methylenedioxymethamphetamine neurotoxicity. J Neurochem. 80(6), 960-969.
19. Hekmatpanah CR, McKenna DJ, Peroutka SJ. (1989) Reserpine does not prevent 3,4-methylenedioxymethamphetamine-induced neurotoxicity in the rat. Neurosci Lett. 104(1-2), 178-182.
20. Mechan AO, Esteban B, O'Shea E, Elliott JM, Colado MI, Green AR. (2002) The pharmacology of the acute hyperthermic response that follows administration of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') to rats. Br J Pharmacol. 135(1), 170-80.
21. Carvalho M, Carvalho F, Bastos ML. (2001) Is hyperthermia the triggering factor for hepatotoxicity induced by 3,4-methylenedioxymethamphetamine (ecstasy)? An in vitro study using freshly isolated mouse hepatocytes. Arch Toxicol. 74(12), 789-793.
22. McNamara R, Kerans A, O'Neill B, Harkin A. (2006) Caffeine promotes hyperthermia and serotonergic loss following co-administration of the substituted amphetamines, MDMA ("Ecstasy") and MDA ("Love"). Neuropharmacology. 50(1), 69-80.
23. Oberlender R, Nichols DE. (1990) (+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine as a discriminative stimulus in studies of 3,4-methylenedioxy-methamphetamine-like behavioral activity. J Pharmacol Exp Ther. 255(3), 1098-1106.
24. Johnson MP, Nichols DE. (1991) Combined administration of a non-neurotoxic 3,4-methylenedioxymethamphetamine analogue with amphetamine produces serotonin neurotoxicity in rats. Neuropharmacology. 30(7), 819-822.

Theres a ssection on COX in the middle + it expands the original

 

[Darksidesam]

The reason serotonin precursors like L-tryptophan and 5-hydroxytryptophan (5-HTP) are neuroprotective, is because they increase serotonin levels after the roll, giving the toxic metabolites more competition, and making it harder for them to get into the cell.

I'm seeing a long long list of chemicals also that you suggest for taking afterwards.
I however, have a different approach. Food and Sunlight.

Dark Chocolate (60% cocoa minimum)
Chicken
Turkey (*Myth*one of the best foods at raising serotonin, and my theory why people fall asleep after a chistmas dinner is that it raises your serotonin levels that high after eating so much turkey)
Tuna
High omega 3 foods that increase serotonin like wild salmon, sardines or Mackerel
High Quality Eggs
Cheese
Bananas
Whey protein (Like that in protein shakes)
Sour Cherries - Raises Serotonin levels + Melotonin , Helps you sleep. Reccomend taking after a Roll.
Free Range Beef
Asparagus
Avocado
Pecans
Pineapple
Eggplant
Spinach
Walnuts

The main ones i eat are Tuna, Dark chocolate, Cheese, Bananas, drink lots of milk and eat free range eggs.
Before i ever used my e-diet, id really suffer on tuesday, that would literally feel like 'suicide tuesday'

However, when i eat the foods on my list i dont experience it at all , or very very minor feelings,
However i have also found if i stop eating the foods say, thursday, I get at least half of the feelings i would on tuesday than if i didnt eat any of these serotonin raising foods.

See More:
http://www.bluelight.ru/vb/entries/...equire-lower-dose-and-lessen-have-no-comedown.

 

[First Bad Comedown]

A truly excellent write-up.
I have not seen such an effective translation into plain English before.

After reading the first section I was about to start shouting that metabolites deserve more than a passing mention.
Thioether metabolites resulting from the primary brain anti-oxidant, gluthianone, are thought to be the most destructive.
But then the second entry goes on to include 2,5-bis(glutathion-S-yl)-alpha-methyldopamine.

Since it has been established that metabolites are likely the source of damage, it is reasonable to suggest that methods of protection could render MDMA use 'safe'. However, there is only a single mention of Serotonin Syndrome.
This is the only weakness I can see, but it is a glaring one.

It may well be that risk of SS results from 5-HT degeneration.
Many case reports of delayed onset SS, 2-3 days after MDMA, exist.
This warrants attention, as the timing of the second serotonin agent may be critical not only to prevent neurotoxicity but also subsequent lethal interactions!

In experienced MDMA users, this risk may be increased if serotonin transmission is already compromised.
And even in new users, the risk still exists - esp. if the second serotonin agent is taken PRIOR to MDMA.
An SSRI or tramadol taken before MDMA could prove a horrible death for an unwitting drug user.

The writer does indicate the proper timing, but I always believe in CAPS or some other method of stressing what is important.
And what about RE-DOSING?

The neuro-protective model here falls flat when additional doses of MDMA are consumed.
Subsequent doses are KNOWN to increase neurotoxicity substantially, so it can be assumed that they do this by increasing the toxic metabolites.

My moto on BL is always - NO RE-DOSING.

As with any research presented for public consumption, it is always easy to find weakness.
Everyone is a goddamn critic, but few are truly qualified.
I must repeat my support and appreciation to the author.
Well done.

 

[till101]

does anybody here is studying and doing xtc frequently ? have you experienced any memory impairment because of mdma ?

 

[elemenehei]

I was looking at Hydroxytyrosol at wikipedia so i copy paste

""""""""""""Hydroxytyrosol (3,4-dihydroxyphenylethanol; DOPET) is a phytochemical with antioxidant properties. After gallic acid, hydroxytyrosol is believed to be one of the most powerful antioxidants. Its oxygen radical absorbance capacity is 40,000 umolTE/g, which is ten times higher than that of green tea, and two times higher than that of CoQ10.[citation needed]

In nature, hydroxytyrosol is found in olive leaf which is used for medical purposes, with immunostimulant and antibiotic properties[1]. It also exists in olive oil, in the form of its elenolic acid ester oleuropein and, especially after degradation, in its plain form. Oleuropein, along with oleocanthal, are responsible for the bitter taste of extra virgin olive oil. Hydroxytyrosol itself in pure form is a colorless, odourless liquid. The olives, leaves and olive pulp contain large amounts of hydroxytyrosol (compared to olive oil), most of which can be recovered to produce hydroxytyrosol extracts.

Studies have shown that a low dose of hydroxytyrosol reduces the consequences of sidestream smoke-induced oxidative stress in rats.[2]

Hydroxytyrosol has been demonstrated to be a monoamine oxidase inhibitor (MAOI). It functions as a potent inhibitor of monoamine oxidase B.[3]

In the brain, it degrades to Homovanillyl alcohol, via COMT.

Hydroxytyrosol is also metabolite of the neurotransmitter dopamine.

Ex vivo data provide the first evidence of neuroprotective effects of oral hydroxytyrosol intake. Both, ex vivo and in vitro studies identified mitochondria as one target for hydroxytyrosol's preventive effects in the brain. [4][5]
1.^ Pinelli et al. Quali-quantitative analysis and antioxidant activity of different polyphenolic extracts from Olea europea L. leaves, 2000.
2.^ Visioli F, Galli C, Plasmati E, et al. (2000). "Olive phenol hydroxytyrosol prevents passive smoking-induced oxidative stress". Circulation 102 (18): 2169–71. PMID 11056087.
3.^ Natural products and derivatives thereof for protection against neurodegenerative diseases
4.^ Schaffer S, Potsdawa M, Visioli F, et al. (2007). "Hydroxytyrosol-rich olive wastewater extract protects brain cells in vitro and ex vivo". J. Agricul. Food Chem. 55 (13): 5043–5049. doi:10.1021/jf0703710.
5.^ Schaffer S, Müller WE, Eckert GP (2010). "Cytoprotective effects of olive wastewater extract and its main constitute hydroxytyrosol in PC12 cells". Pharmacol. Res. 62 (4): 322–327. doi:10.1016/j.phrs.2010.06.004. PMID 20600919.""""""""""""""

So MAO-B + antioxidant "MAKE SOME OLIVE LEAF TEAAAAAAAAA" and an aspirin pre roll

I will research more exact consentration in leaves. amount for full mao -b inhibition

 

[MazDan]

Bucklecroft, could you provide information as to where you came by this article please as an acknowledgement is important. Such information should be provided at the very top of each post.

Cheers.

 

[Bucklecroft Rudy]

* LINKS REMOVED AT AUTHOR'S REQUEST*


Apologies assumed crediting the author was enough

 

[atrollappears]

Mmmm I don't see any citations about COX significantly mediating MDMA induced damage, and that bit about COX metabolizing MDMA is almost certainly false.

There is a good reason to believe that a COX inhibitor would reduce MDMA induced neurotoxicity, which is that MIN is probably mediated by inflammatory processes (microglial activation), and COX inhibitors (aspirin, ibuprofen) are obviously anti-inflammatory. However it turns out that COX inhibition doesn't provide any significant protection against methamphetamine neurotoxicity, which is similar to MIN in many ways, including being mediated by inflammation/microglial activation. This, in my mind, casts doubt on the usefulness of COX inhibition to reduce MDMA neurotoxcity. Interestingly, though, and fortunately, ibuprofen does decrease meth neurotoxicity even while aspirin doesn't. The reason for this is that ibuprofen also activates the PPR receptor gamma, which itself decreases inflammation and subsequent damage.

So basically, take ibuprofen (or ketoprofen), not aspirin.

Citations:
"Reduction of nuclear peroxisome proliferator-activated receptor gamma expression in methamphetamine-induced neurotoxicity and neuroprotective effects of ibuprofen." Tsuji T, Asanuma M, Miyazaki I, Miyoshi K, Ogawa N.
http://www.ncbi.nlm.nih.gov/pubmed/18946735

"Methamphetamine-induced neurotoxicity in mouse brain is attenuated by ketoprofen, a non-steroidal anti-inflammatory drug." Tsuji T, Asanuma M, Miyazaki I, Miyoshi K, Ogawa N.
http://www.ncbi.nlm.nih.gov/pubmed/14615038

Oh, and sorry for reviving an old thread