Health - THE ECSTASY MANIFESTO - Can MDMA Use Be Made Safer?

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    Health Information from Natural Solutions Radio -- THE ECSTASY MANIFESTO - Can MDMA Use Be Made Safer ?

    3, 4 -methylenedioxymethamphetamine (MDMA, MDM, Adam, Ecstasy, XTC, e, X, Roll, Molly) is a methamphetamine analog with novel properties. It is frequently referred to as a chemical hybrid of amphetamine and mescaline, although pharmacologically it is quite different than either of its structurally related cousins.

    January 17, 2004
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    Category: Drug Wars
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    For informational and research purposes only.

    I. INTRODUCTION

    A. Background

    B. Modern usage

    II. SHORT TERM EFFECTS AND DISPOSITION

    A. Serotonin effects

    B. Dopamine effects

    C. Pharmacokinetics

    III. LONG TERM EFFECTS OF MDMA

    A. Depletion of tryptophan hydroxylase to form serotonin

    B. Up and down regulation of serotonin

    C. Chronic serotonin underfunctioning in humans

    D. Neurotoxic effects in animals

    E. Neuronal growth and reorganization

    IV. MDMA NEUROTOXICITY

    A. Events leading to MDMA neurotoxicity

    B. Oxidative damage to neurons by MDMA

    C. Failure of self-protective mechanism

    D. Estimating a level of human neurotoxicity for MDMA

    V. PROTECTIVE COUNTERMEASURES

    A. Antioxidants that deactivate MDMA-generated toxic oxygen species

    1. Glutathione Peroxidase and Selenium

    2. N-Acetyl Cysteine (NAC)

    3. Ascorbic Acid (Vitamin C)

    4. Melatonin

    5. Alpha Lipoic Acid/ R-Lipoic Acid

    B. Nutraceutical Neuroprotective Substances

    1. 2-Amino-ethanol phosphate (2AEP)

    2. 5-Hydroxy tryptophan (5HTP)

    3. Vinpocetine

    4. Idebenone and CoQ10

    5. Ginkgo Biloba Extract

    C. Pharmaceutical Neuroprotective Substances

    1. Hydergine and Sermion

    2. Piracetam

    3. Deprenyl

    4. Bromocryptine

    5. SSRI’s (Prozac)

    D. Preventing Hyperthermia

    E. Improving neural bioenergetics

    F. Establishing a safe MDMA dosage

    VI. BEHAVIORAL AND NEUROPSYCHIATRIC EFFECTS OF MDMA

    A. Adverse behavioral and psychological effects

    B. Beneficial behavioral and psychological effects

    C. Withdrawal, tolerance and dependence to MDMA

    VII. MDMA AND CHRONOBIOLOGICAL DESYNCHRONIZATION

    A. Effects of chronobiological desynchronization

    B. Chronobiotic agents to stay in sync

    I. INTRODUCTION

    A. Background

    3, 4 -methylenedioxymethamphetamine (MDMA, MDM, Adam, Ecstasy, XTC, e, X, Roll, Molly) is a methamphetamine analog with novel properties. It is frequently referred to as a chemical hybrid of amphetamine and mescaline, although pharmacologically it is quite different than either of its structurally related cousins. (1-2)The parent compound, MDA, was synthesized by a German chemist named Paul Hoering in the late 1890’s. It is unknown what his connection, if any, was to the German pharmaceutical company, Merck, or if he was aware of the psychoactive properties of his product. MDA and MDMA were submitted for patent by Merck in 1912. MDMA was a synthetic intermediate in the preparation of the vasoconstrictor hydrastatin. Merck subsequently was granted the patent in 1914. Contrary to popular myth, MDMA was never designed or marketed as an appetite suppressant. The psychoactive properties of MDA were discovered by Gordon Alles in 1932. (2b)

    To our knowledge, the first mention of the psychoactive properties of MDMA was in Michael Valentine Smith’s Psychedelic Chemistry first published in 1974. (3)

    "N-methyl-MDA is extremely pleasant, producing more euphoria than cocaine, lasting much longer and having a very easy down."

    There is a persistent rumor from several researchers tracking the early history of MDMA that there was a large scale distribution network in New England during the early 70’s that managed to introduce the drug to hundreds of thousands of people and maintain their anonymity. (4) Dr Shulgin references the forensics journal, Microgram, reporting the identification of MDMA, in 1972. (5)

    Dr Shulgin is frequently referred to in the popular press as "the grandfather of Ecstasy", but reported in PIHKAL that he learned of the unique (emotional) properties of MDMA in the mid 1970’s by a female graduate student at UC Berkeley, named "Merrie Kleinman". Shulgin’s alter ego, Shura Borodin reports:

    "This was not the first time I had heard mention of MDMA. In fact, I had synthesized it back at Dole in 1965 but had never before met someone who had personally tried it .I re-synthesized it and found it unlike anything I had taken before. It was not psychedelic in the visual or interpretive sense but the lightness and warmth of the psychedelic was present and quite remarkable."(6)

    He subsequently co-authored (with Dr David Nichols) the first peer reviewed report of the effects of MDMA in an article entitled "The Characterization of Three New Psychotomimetics" in 1978 (7).

    MDMA has a higher threshold level than does MDA, but otherwise it is very similar in potency. Within the effective dosage range, 75-150mg orally, the effects are first noted very quickly, usually within a half hour following administration. With most subjects the plateau of effects is reported to occur in another half to (one) hour. The intoxication symptoms are largely dissipated in an additional 2 hours except for mild residual sympathomimetic stimulation which can persist for several additional hours. There are few physical indicators of intoxication and physiological sequelae are virtually non existent. Qualitatively, the drug appears to evoke an easily controlled altered state of consciousness with emotional and sensual overtones. It can be compared in its effects to marijuana, to psilocybin devoid of the hallucinatory component, or to low levels of MDA.

    Dr Shulgin introduced it to the retired psychiatrist, Dr Leo Zeff (The Secret Chief). Dr Zeff had extensive experience with "psychedelic psychotherapy." He was so impressed with the therapeutic potential of MDMA that he came out of retirement and began training therapists in protocols for MDMA assisted psychotherapy. Between 1977 and 1985, MDMA was used by psychotherapists in biweekly regimens as an adjunct in the treatment of a variety of otherwise difficult to treat conditions. MDMA was reported to be especially useful in treatment of PTSD (rape victims and war veterans), in couples counseling and in fear resolution in the terminally ill. The breakthroughs possible with MDMA led one psychiatrist to state that a single session with MDMA was comparable to five years of therapy without it. (8)

    At the psychedelic conference in Santa Barbara (1983), Shulgin gave a speech entitled "Why I Do What I Do." By this time, the compound had already been experienced by many of the attendees who broke into a roar when he mentioned it. (9)

    "This substance is unique among those so far discovered. It produces a mild, easily controlled altered state of consciousness characterized by empathy, euphoria, and an overall sense of well being. It is short acting (4-6 hours) and allows one to temporarily lower psychological defenses without any threat to the ego."

    In the 1980’s, MDMA grew in popularity as a recreational drug, especially in Texas, where it was being marketed in "Tupperware Style" parties. It could be bought openly in clubs, be delivered by waiters and charged on credit cards. (10) The "entrepreneur" responsible for the Texas scene and the widespread dissemination of MDMA first heard about MDMA at the Santa Barbara conference. He also claims to be the person that nicknamed it "Ecstasy", and used the aka "Ram" (a Hindu name of God). He was later indicted and convicted of smuggling MDMA into the US and was financier of an international Ecstasy Operation that had a large-scale production facility in the heart of Brazilian Sassafras country. After cooperating with the DEA to get convictions on more than 50 people, including people he dealt with when MDMA was still legal, he served four years in Federal prison where he became a self proclaimed "enlightened master." Upon release he began traveling the world teaching his flock about the evils of drugs and the attainment of "4th dimensional consciousness."(11)

    Due to the increasing popularity and perceived threat to public health, as a result of George Ricaurte’s published report of the neurotoxicity of MDA in rats, the DEA banned MDMA on July 1, 1985. It was consigned to the Schedule I category of the Controlled Substance Act, meaning it had a high potential for abuse, no accepted medical value, and no safe usage even under medical supervision. (12) George Ricaurte, then a graduate student at the U of Chicago has since made a lucrative career as the government’s leading expert on MDMA neurotoxicity. His close ties to NIDA, NIMH and the DEA has led several prominent researchers to question his personal and scientific integrity. He was recently ridiculed by peers when he suggested that MDMA might cause Parkinsonism later in life. (13)

    In 1986, Dr Nichols first coined the term "entactogen", meaning "to touch within", in order to describe the novel properties of MDMA. Nichols and his research group provided evidence that MDMA was the prototype of a new family of compounds, pharmacologically distinct from amphetamines and psychedelics. (14)

    B. Modern usage

    By the mid to late 1980s, interest in MDMA spread from the United States across the Atlantic to Europe and back to the United States. Today, MDMA is one of the most widely used "recreational" drugs worldwide. There are also reports of widespread use in Japan, China, Brazil, Bali and India.

    It was estimated in 1990 that 4% of U.S. college students had experimented with MDMA In 1996 it was reported that 13% of British University Students had used MDMA. The National Household Survey on Drug Abuse in conjunction with the National Institute for Drug Abuse estimated that in 1995 and 1996 over 6.5 million people in the United States over the age 12 were users of MDMA. In 1997 of the 216 million people represented, 1.5% were users. The highest percentage occurred in the 18 to 25 year old age bracket. The current level of worldwide MDMA usage may be increasing exponentially. (15-17)

    In 1998, there were 750,000 pills seized in the US. In 1999 that number climbed to 3.5 million seizures, and in the first half of 2000 there were 4 million confiscations. If that trend continued, so that by the end of 2000 the number of confiscations went to 8 million and the general rule of the DEA bore out; seizure of ~1/10 of what gets through, then 80 million pills were consumed in the US. That means about one in four people consumed MDMA in the US in 2000. (obviously, some people ate more than their share) (18)

    MDMA has been described as having "the greatest growth potential among all illicit drugs" in the United States. Tens of thousands of new users are being introduced to MDMA every month. MDMA has initiated a culture similar to the impact of LSD in the seventies. This is very evident by the dramatic increase in raves (all night dance parties) and widespread usage by the X-generation. (19)

    II. SHORT TERM EFFECTS AND DISPOSITION

    MDMA is a ring-substituted amphetamine. A common feature of the amphetamine compounds containing a "methylenedioxy" group (between positions 3 and 4 of the benzene ring) is stimulating the release of serotonin (5HT) and dopamine (DA) from the presynaptic vesicles and inhibiting of reuptake of these neurotransmitters. (Figure 2) The combined release of 5HT and DA produces the desired "entactogenesis", and contributes to the selective serotonergic neurotoxicity. Researchers have proven that the desired effects can be separated from the subsequent neurotoxicity by blocking or attenuating oxidative stress.

    When a dosage of MDMA (1.5-2 mg /kg of body weight) is ingested on an empty stomach, effects begin in 30-45 minutes. The primary psychoactivity reaches a plateau 60 to 90 minutes after ingestion, lasts for about two hours and gradually tapers off over 4 to 6 hours. The "afterglow" may last for several days, and the insights and problem resolution achieved during the experience may persist, indicating that true integration has taken place (20-22). The integration seems to be separate from the pharmacological properties of the drug, and is why therapists believe MDMA holds so much promise in treatment of psychiatric difficulties. The relatively short duration encourages many naïve users to "chase" the first high with subsequent boosters. The potential problems with this approach are discussed in detail below and involve disproportionate plasma level increases due to nonlinear pharmacokinetics and increased oxidative stress.

    A. Serotonin (5HT) effects

    The complex actions of MDMA on serotonergic (5HT) and dopaminergic (DA) neurons produce entactogenesis, empathogenesis, psychedelic effects and sympathetic stimulation.

    § Entactogenesis is a state of reduced anxiety, and defenses coupled with euphoria, empathy, self acceptance (and acceptance of others) and peacefulness.

    § Empathogenesis is a feeling of emotional closeness to others coupled with a breakdown of personal communication barriers. The unconscious filter between what you want to express and what you actually say is removed. Open communication occurs without fear or anxiety. One can be completely open without feeling vulnerable or in danger.

    § Psychedelic effects are sensory enhancements of touch, taste, smell, vision and hearing. There are also alterations in interpretation and meaning of common objects or events.

    As mentioned above, these unique psychotropic effects of MDMA and its analogs (MBDB, BDB, and MDE) have led experts to propose that entactogens are a distinct pharmacological class of substances. They exert different effects than either amphetamines or psychedelic phenethylamines like mescaline, or 2C-B. (23)

    As MDMA is metabolized and/or excreted and the 5HT depleted from the 5HT terminals, the user "comes down." Several hours after administration of a single high dose of MDMA, a reduction of as much as 80% of intracellular 5HT occurs in experimental animals. (24) Since the extent of 5HT release is directly proportional to dosage, it is improbable that 5HT reductions are as extensive in human users.

    During the "coming down" phase, lower levels of serotonin and reduced serotonin receptor activation may create a state of anxiety, irritation, tiredness, depression, mental impairment and antisocial behavior. This is especially true when subsequent "boosters" are taken in order to try to regain or "chase" the initial magic.

    The process of serotonin release is mediated by the interaction of MDMA with 1) the vesicles that store serotonin and 2) the serotonin reuptake transporter on the axonal membrane leading to increased levels of serotonin in the extracellular spaces of the brain. MDMA enters the presynaptic nerve terminal to exchange with serotonin stored in vesicles, causing the release of serotonin into the extracellular space by the transporter. A current theory suggests that MDMA enters the reuptake transporter and makes it work in reverse by transporting serotonin from inside the axon into the synapse. After the reuptake transporters remove the serotonin, the serotonin is metabolized by the enzyme monoamine oxidase A. (25-28)

    Researchers have found that MDMA is a partial agonist of the 5-HT2A and 5HT2C receptors in the central nervous system. The 5-HT2A serotonin receptors play a major role in hallucinogenic activity as well as mood regulation, behavior, and sexual activity. Evidence from biochemical, electrophysiological, and behavioral studies has shown that the two major classes of psychedelic hallucinogens--the phenethylamines, like DOB and DOI, and the indoleamines, like LSD--are agonists for the 5-HT2 receptors. (29-30) Activation of the 5HT2A receptor with another psychedelic is a frequently used protocol described in detail in PIHKAL. Interestingly, this activation is also implicated in the neurotoxicity, suggesting that risk may be increased by taking a psychedelic prior to or even after consumption of MDMA. The connection between 5HT2A activation and neurotoxicity is poorly understood, but is associated with the subsequent increase in DA synthesis and release leading to oxidative stress. Recently it was suggested that the mechanism of action of the classical psychedelics such as LSD, involves 5HT2A activation which may increase neuroplasticity by gene activation and subsequent increases brain–derived Neurotrophic factor (BDNF) in the neocortex. (30a) This could explain why Dr Albert Hofmann, the discoverer of LSD believed that sub hallucinogenic doses of LSD act as a powerful "smart drug", encouraging re-organization of higher brain structures.

    B. Dopamine (DA) effects

    Release of dopamine from dopaminergic presynapses by MDMA creates (in addition to the desired entactogenesis) acute amphetamine-like stimulatory effects. Stimulation of the sympathetic nervous system causes increased heart rate and blood pressure, hyperactivity followed by fatigue, hyperthermia (increased body temperature), dry mouth and trismus/bruxism (jaw clenching). Most of these effects subside within 24 hours. Persistent jaw clenching is reported by ~25% of users, and may last up to a week unless remedies are taken. (31-32)

    Hyperthermia is a major feature in high dose recreational MDMA users (especially in an all night dance environment) and contributes towards increasing the toxic potential of MDMA. The hyperthermic and behavioral responses to MDMA are triggered by activation of serotonin and dopamine transporters and receptors. Large-scale release and later reduction (depending on dosage) of stored serotonin occurs during the first few hours after high doses of MDMA are consumed. MDMA itself does not directly increase core temperature, but affects the thermoregulatory mechanisms, making a person under its influence susceptible to the ambient temperature. High ambient temperatures, dehydration and loss of electrolytes are known to increase the neurotoxic potential of the drug.

    The MDMA-stimulated release of dopamine has been proposed to occur by either (1) direct stimulation of MDMA on dopamine transporters, or by (2) indirect stimulation via the 5HT2A receptors which regulate GABA interneurons. When the GABA interneurons are "shut off" there is an increase in synthesis and release of DA. In experimental studies, rats that were given MDMA had five times more extracellular dopamine than controls. This increase in DA releases excessive hydrogen peroxide as it is metabolized by MAO-B. Hydrogen peroxide reacts further to form the dangerous hydroxyl radical significantly increasing oxidative stress and possible neurotoxicity.

    MDMA is highly efficient at releasing 5HT and DA due to its use of both the dopamine (DAT) and serotonin transporters (SERT) to cross cell membranes and due to its highly lipophilic nature; it can easily diffuse across the non-polar lipid membrane of the cell.

    Within 24 hours after a single injection of a high dose of MDMA in serotonin- and dopamine-deficient rats, the greatly reduced levels of serotonin and dopamine are restored to "normal" levels. Thereafter, serotonin declines progressively. After multiple doses of MDMA have been administered to rats, serotonin levels are reduced for more than a year, depending on which species and part of the brain are tested. (33-34)

    C. MDMA Pharmacokinetics (PK)

    Pharmacokinetics (PK) is the study of the movement of a drug through the body; as affected by route of administration, uptake, distribution, elimination and biotransformation. Billions of doses of MDMA have been consumed since the mid 70’s, but until recently very little was known about PK in man. The Spanish government recently permitted PK evaluation on human volunteers. Several studies were reported by the same research group that developed a validated method for measuring MDMA and its metabolites in plasma and urine. (35-37)

    MDMA was administered in dosages between 50 and 150mg. The tmax (time of maximum plasma concentration) =2 hours. The Cmax (maximum plasma concentration at tmax =222.50ng/ml plasma. The AUC (area under the curve from 0-24 hours representing total plasma concentration, showing the change over 24hours) is 2431.38 ng/ml.h-1. The t1/2 (the elimination ½ life=the time for ½ of the parent drug to be eliminated)= ~ 9hours.

    One of the most significant finds was that at dosages slightly above the average human dose the pharmacokinetic parameters become non-linear, i.e. a slight increase in dose produces a disproportionate increase in plasma and urine levels. (38) For this reason as well as the observation of cardiovascular and "subjective" side effects at the 150mg range, the researchers refused to administer higher doses to more than the two subjects tested at this level. This fact is extremely important considering that even in a therapeutic context initial doses were usually in the 125-150mg range followed by a booster 3 hours later with 60-75mg (usually ½ the original dose). Additionally, recreational users may take several pills during the course of an evening or weekend.

    The non-linear PK is believed to be the result of saturation of the hepatic CYP450 enzymes responsible for the first phase of MDMA metabolism. A possible result of this is that dangerous blood levels can be reached quickly which can lead to adverse (serotonin syndrome) and life threatening reactions, as well as substantially increasing the neurotoxic potential. Our research has shown that 150mg doses significantly increase oxidative stress for prolonged periods of time.

    The PK researchers also discovered that plasma concentrations of MDMA showed a 13% increase after the use of alcohol (0.8g/kg) whereas plasma concentrations of alcohol showed a 9 to 15% decrease after MDMA administration. The MDMA-alcohol combination induced longer lasting euphoria and well being than MDMA or alcohol alone. (39) Another study in rats showed that MDMA diminished the rewarding quality of alcohol. (40)

    III. LONG TERM EFFECTS OF MDMA

    A. Depletion of tryptophan hydroxylase to form serotonin

    Activity of tryptophan hydroxylase, the rate-limiting enzyme required to form serotonin from its dietary precursor, L-tryptophan, is greatly reduced after repeated large doses of MDMA. This is due to oxidation of key sulfhydryl groups of the enzyme. The reduced activity of tryptophan hydroxylase may take up to two weeks to return to normal. (41)

    B. Up and down regulation of serotonin

    MDMA causes post-synaptic serotonin 5-HT2 receptors in the brain to up-regulate or down-regulate according to the dose. Up and down-regulation are normal adaptive responses to increased transmission through the serotonin receptors, as a result of MDMA-stimulated serotonin release.

    § Small doses of MDMA (equivalent to a human dose of <1mg/kg) cause up-regulation. This appears to stimulate the development of new serotonin neurons.

    § Higher doses of MDMA (equivalent to a human dosage of 2 mg/kg) may cause down-regulation. The down-regulated receptors decrease both the binding of serotonin and the psychotropic effects of MDMA. Down-regulation protects receptors from damage by overstimulation and maintains homeostatic balance in the brain through feedback control of serotonin transmissions and receptor sensitivity in the neural network. (42-46) Down regulation, rather than neurotoxicity may account for the "loss of the magic" after repeated exposure to MDMA.

    C. Chronic serotonin underfunctioning in humans

    In humans, the excessive recreational use of MDMA may result in subnormal serotonergic function. Serious behavioral and psychological consequences may result from high dose and frequency exposure. In animals, the long-term administration of high doses MDMA may result in a degeneration and loss of serotonergic axon terminals and 5HT binding sites. (47-51)

    Sub optimal functioning of the 5HT system occurs through several separate but different interacting mechanisms (52-55):

    1) MDMA depletes serotonin stored in neurons as it is metabolized.

    2) MDMA decreases activity of the enzyme tryptophan hydroxylase for an extended length of time. This impairs the ability of the cell to make serotonin and to replace the MDMA-depleted stores.

    3) MDMA causes the serotonin 5HT2 receptors in the brain to temporarily down regulate and prevent serotonin from binding to the cell receptor sites.

    4) MDMA reduces the activity of both the 5HTIA and 5HT2 receptors.

    Among all the chemical neurotransmitters, serotonin is most involved in the etiology or treatment of disorders of the central nervous system. These include disorders of appetite, sleep, memory, learning, temperature regulation, mood, behavior (including sexual and hallucinogenic behavior), cardiovascular function, muscle contraction, blood pressure, pain and endocrine functions. Evidence suggests that every one of these disorders can be treated by either

    (1) Mimicking the actions of serotonin

    (2) Enhancing its supply

    (3) Blocking its action

    Serotonin is a molecule that is found in both the plant and animal kingdoms. The human body produces serotonin from the dietary amino acid tryptophan that is found in many foods. The body uses the enzyme tryptophan hydroxylase to convert dietary tryptophan into the amino acid 5-hydroxytryptophan (5-HTP). 5-HTP enters serotonin cells directly through the cell membranes. Once it is in the axon, the readily available enzyme, carboxylase transforms 5-HTP into serotonin. Subsequently, serotonin is stored in presynaptic vesicles for release in response to an electrical impulse travels the length of the axon. The serotonergic system is so sensitive that natural variations in serotonin levels among animals on a normal diet can affect their behavior in profound ways. (56-59)

    A functional deficiency of serotonin from the overuse of MDMA or from existing psychological problems may produce one or many symptoms of a "serotonin deficiency syndrome" that manifests as cognitive, emotional and behavioral disturbances. These types of problems have been observed in MDMA users. In human research, MDMA produced significant mood changes (dysphoria, tiredness and guilt), aggressive-impulsive behavior and depressive traits during the first three weeks after drug discontinuation (60).

    Animal research has confirmed that that the long-term depletion of brain serotonin by MDMA is accompanied by impairments in serotonin-related function. Researchers noted deficits in neurochemical, thermal and behavioral responses to subsequent MDMA administration (61 ) Other studies have reported a loss of up to 90% of the brain’s 5HT with no observed behavioral difficulties, suggesting that the remaining 5HT cells adapt and take over the function of the lost or depleted cells. (61a)

    The symptoms of low serotonin include anxiety, depression, agitation, obsessiveness, migraines, panic, overeating, memory loss, muscular pain, nausea, PMS, phobic behavior and other disturbances. Exactly which symptoms, if any, appear in a single MDMA user depends upon a variety of factors. Problems of a serotonin deficiency syndrome are related to

    (1) Pre-existing conditions

    (2) The dose and frequency of MDMA use

    (3) The interaction with other drugs

    (4) Environmental factors

    (5) Derangements in neurotransmitter activity

    A chemical imbalance in neurotransmitters may cause individuals to unconsciously choose MDMA as a sort of ‘self-medication’ for their disorder. This fact demonstrates clearly why it is inhumane to criminally punish MDMA users.

    D. Neurotoxic effects in animals

    Numerous studies have demonstrated that administering large doses of MDMA to several species results in a long-lasting degeneration of serotonergic axons and axon terminals in several regions of the brain, especially those of the dorsal raphe. Some regrowth may occur after MDMA use is terminated, but it is a slow process that takes years. The new neurons have a 30-50% decrease in synaptic density and exhibit re growth patterns that are distinct from the originals. (62-66) Researchers have speculated that this may actually be a form of chemically induced selective pruning of forebrain 5HT neurons. One of the results of this may be less aggressive behavior.

    Many variables, including dose, route of administration and individual biochemistry determine the extent to which MDMA neurotoxicity will be observed. MDMA-induced neurodegeneration is closely related to the dose and frequency of administration. Unfortunately there is no way to determine in advance what the individual susceptibility to a given dose may be. Although rare, adverse reactions have occurred with even a low single dose. In general, repeated administration of MDMA is considered to be more neurotoxic than a single dose.(67-68)

    In an attempt to control the spread of MDMA amongst young people (a phenomena the authorities have called an "epidemic"), the DEA has decided to disseminate misleading and pseudoscientific information by liberally "spinning" the results of Ricaurte’s research to suit their objectives. (69)

    MDMA is toxic to human brain cells; there is absolutely no "window of safety" between a dose of MDMA found in a single tablet sold on the street and the threshold dose that causes brain cell death in humans. While cell death occurs from the first exposure to MDMA, its functional effects may not be seen for months.

    We do not deny that MDMA may be potentially dangerous and we commend our government in their attempt to keep psychoactive drugs away from children, but deplore their tactics and blatant disinformation. It is this type of "drug education" that leads young people to distrust authorities. This type of "scared straight" tactic generally backfires and leads anyone above 8 years old to engage in the very behavior the report is attempting to discourage. The government can not contend to have public health as their primary concern while simultaneously implementing policies and disseminating these types of statements, that will surely cause more distrust and lead to greater harm.

    No credible scientific research has established conclusively that MDMA is "toxic" to human brain cells, especially at the minimally effective doses or after a single use. As mentioned above the potential may exist for a given, susceptible individual, but can not be considered a general property of the drug. Most researchers believe that repeated exposure increases the likelihood of an adverse reaction, or of long term changes in the 5HT system.

    The DEA report claims that an average street dose is 100mg. While the average is 95 mg according to pill testing results, the range is 70-120mg.

    According to the primary researcher of the UCLA MDMA study, Dr Charles Grob:

    In a study with more relevance to the single time or occasional use, low dose therapeutic model, a no effect level in monkeys of 2.5 mg/kg MDMA administered orally every two weeks for four months (totaling 8 times) was established by Ricaurte. Either because of the highly politicized nature of the MDMA neurotoxicity debate, or for reasons that have as yet not been made entirely clear, this information has to date never been published in the mainstream scientific literature.(70)

    2.5mg/kg for a 70kg (154lb) man equals 175mg of MDMA which is above the range found in street tablets. Interestingly, a recent study in Spain demonstrated that in rats, 4mg/kg 2 times per day for several days were required to induce neurotoxicity (equal to 560mg/day for a 70kg man). (71) Dr Vollenweider claims (based on clinical observations in Switzerland) a person could consume 1.7mg/kg without exceeding the endogenous self protective mechanisms. He also cites animal based research that showed a single dose of 5mg/kg revealed no damage to the 5HT system (72) While we believe this dosage (5mg/kg) is on the high side, it highlights the inadequacy of a law enforcement agency’s attempt to "interpret" science.

    Dr Grob also points out that "the neurotoxicity is not inextricably linked to the acute effects of the drug". (73) The government (for understandable reasons) has completely neglected to report the animal studies that showed antioxidants such as lipoic acid, vitamin C, cysteine and alpha-phenyl tert-butyl nitrone (PBN) completely blocked neurotoxicity. It would seem that the government is not content to frighten those who have never used MDMA but is also attempting to scare people with the thought of permanent brain damage even if they have used the drug only once (punishment by fear…after the fact). While Ricaurte has proposed the "roll now…pay later theory", there is no evidence that a single low dose will have "functional" consequences months later. In fact, studies of MDMA users generally found very subtle changes in memory or performance even after MDMA had been used hundreds of times. Dr Grob states:

    "While subsequent studies have reported decreased performance in some memory tests, these decreases are generally less than one standard deviation point below the scores of the controls (a difference which is not considered even borderline impairment by clinical neuropsychologists)." (74)

    E. Neuronal growth and reorganization

    In contrast to the administration of high doses of MDMA that act as a selective serotonergic neurotoxin in animals, the administration of low concentrations of MDMA produce the opposite effect, stimulating neuronal growth. MDMA’s release of serotonin modulates receptor enzymes and stimulates astrocytes to release Neurotrophic Growth Factors (NGF). These actions, in turn, cause neurons to develop and innervate new target areas in the brain. (75-77)

    Stimulating neurons to morphologically reorganize, known as neuroplasticity, has the potential to correct underlying causes of neurochemical imbalances. It may be possible to re-engineer neuronal structures and activity to create a biochemical state of lasting well being and happiness. (78)

    IV. MDMA NEUROTOXICITY

    For more detailed and technical information regarding the various mechanisms of MDMA neurotoxicity and methods of preventing it, see: The Nutriceutical and Pharmaceutical Approach to Harm Reduction .

    A. Events leading to MDMA neurotoxicity

    The exact mechanisms and details of the sequences of events underlying MDMA neurotoxicity are not completely understood. It is now well established that the selective 5HT neurotoxicity is related to oxidative stress, leading to lipid peroxidation of the 5HT terminals. There is also evidence of protein and DNA oxidation (79-83). This ultimately leads to bioenergetic imbalances that disrupt the cell’s homeostatic mechanisms. Once the homeostats are disrupted apoptotic mechanisms are activated. These homeostats are regulated by the cellular redox status, which alters gene expression. Dr Nichols has proposed that oxidation of DA within the depleted 5HT terminal is essential to the process, and may be summarized as follows:

    1. MDMA induces an acute release of serotonin and dopamine.

    2. This acute release is followed by depletion of intraneuronal serotonin stores.

    3. The initially released serotonin activates post-synaptic 5-HT2A receptors located on GABA interneurons, causing a decrease in GABA transmissions and increase of dopamine release and synthesis.

    4. The excessive dopamine that is released is transported into the depleted serotonin terminal.

    5. Dopamine is de-aminated (metabolized) by monoamine oxidase B within the serotonin terminals. This results in the formation of free-radicals and selective degeneration of serotonergic axons and axon terminals.

    B. Oxidative damage to neurons by MDMA

    The observed degeneration of the serotonergic axon and axon terminals in several regions of the brain from MDMA is most likely the result of a combination of processes.

    Research has focused on:

    1) the generation of toxic MDMA metabolites

    2) the role of endogenous neurotransmitters producing reactive free radical intermediates

    3) the failure of self-protective mechanisms from energy depletion, and excessive free radical production. (84-90)

    · Degradation of MDMA into neurotoxin byproducts

    MDMA is converted into several highly toxic compounds. In rats, MDMA is metabolized into 2,4,5-trihydroxymethamphetamine (THMA) and 2,4,5-trihydroxyamphetamine (THA), that interact with 5-HT reuptake sites and may irreversibly damage the neurons. (91) These metabolites have not been identified in humans. In humans the primary metabolites are 3,4-dihydroxymethamphetamine (HHMA), and 3,4-dihydroxyamphetamine (HMA). (92) These are further metabolized into conjugates with glutathione (cysteine and NAC) which may undergo subsequent oxidation to produce even more potent neurotoxins, benzodithiazines.(93) In vitro, conjugation was completely suppressed with Ascorbic acid (vitamin C). (93a) Ultimately, HHMA and HMA are methylated by COMT, and form conjugates with UDP-glucuronic acid, inorganic sulfate, and glycine. All of these products have been identified in human plasma and/or urine. (94)

    · Degradation of MDMA into free radical generating metabolites

    MDMA is metabolized to catechols, quinones and semi-quinone metabolites in the liver, kidneys, and brain. These highly reactive intermediates produce superoxide and hydroxyl free radicals. They may also damage membranes and inactivate enzymes by forming redox cycling quinoproteins. (95) While most of the research has focused on MDMA induced neurotoxicity, it is now clear that free radical mechanisms are also involved in liver, heart and kidney toxicity. (96)

    · Dopamine-induced oxidative damage

    Dopamine causes oxidative damage to presynaptic neurons when its concentration in the extracellular spaces leads to its use as a substrate for the serotonin transporter. Even small increases in DA can produce oxidative stress and neurotoxic metabolites. (97) This explains why the combination of amphetamine and methamphetamine considerably increases neurotoxicity in combination with MDMA. Nichols also demonstrated that MDAI, a non neurotoxic analog of MDMA that acts as a pure 5HT releaser becomes neurotoxic when combined with methamphetamine. (97a)

    · Hyperthermic pro-oxidative actions

    MDMA prevents regulation of body temperature. This deregulation of the body’s internal temperature causes increased susceptibility to the ambient temperature. High temperatures increase the generation of free radicals in the brain that damages serotonergic terminals and lowers the activity of the rate-limiting enzyme for serotonin production tryptophan hydroxylase. (98)

    · Decreased defenses and increased neuronal oxidative damage

    Neural tissue is more sensitive to oxidative stress damage than other tissues and organs due to its high lipid content. Outer neural and mitochondrial membranes and the myelin sheath are rich in polyunsaturated fatty acids that are prone to peroxidative attack. Damage to serotonergic neurons occurs when oxidative stress and toxic metabolites overwhelm the body’s endogenous free radical scavenging defenses and detoxification mechanisms. (99)

    Studies show that MDMA-induced neurotoxicity involves cascading reactions that generate superoxide radicals, hydrogen peroxide, nitric oxide, peroxynitrite and hydroxyl radicals. (100)

    Superoxide + hydrogen peroxide > hydroxyl radicals

    Superoxide + nitric oxide > peroxynitrite

    MDMA has been shown to increase superoxide levels and is implicated as a key mediator of the neurotoxic cascade, and reveals a point of intervention, blocking the process. The uncontrolled action of hydroxyl radicals and peroxynitrite on serotonergic neurons causes a disruption of cellular energetics and selective withering of the nerve terminals.

    Hydroxyl radicals are highly neurotoxic, and disrupt the cell’s production of ATP by oxidizing key mitochondrial enzymes, and disruption of cellular respiration. (101-103)

    Superoxide, hydrogen peroxide and hydroxyl free radicals are produced as a consequence of normal metabolism. The cells have developed complex mechanisms for keeping these free radicals under control. There is growing evidence that when these free radicals exceed the cells’ ability to neutralize them within the brain, damage occurs and is also implicated in conditions such as traumatic brain injury, ischemia-reperfusion injury, and neurodegenerative diseases such as Parkinson's disease, Alzheimer's dementia, and multiple sclerosis. The site-specific generation of these cytotoxic free radicals from MDMA metabolism, coupled with disruption of cellular homeostats causes the observed degeneration of serotonergic neurons in animals. (104-106)

    C. Failure of the self-protective mechanism (the antioxidant defense shield)

    The overwhelming of the endogenous antioxidant shield may be the most crucial factor causing the observed degeneration of serotonergic neurons and is supported by direct measurement of free radicals and oxidative-stress damage to lipid membranes. (107-109)

    MDMA overtaxes energy metabolism in the serotonin presynapse by substituting for serotonin and dissipating transmembrane ion gradients. An energy deficiency develops that compromises energy-dependent neuroprotective mechanisms that:

    (1) regulate transmembrane-ion exchange

    (2) maintain internal Ca (++)-homeostasis

    (3) prevent oxidative stress

    (4) promote cell detoxification and repair

    Above a certain threshold, failure of self-protective mechanisms leads to a degeneration of the serotonin axon terminal from toxic and reactive free radical molecules leading to an apoptotic cascade (see the molecular details in The Nutriceutical and Pharmaceutical Approach to Harm Reduction .

    Recent studies in rats demonstrated that 4mg/kg 1x/day did not produce the characteristic terminal loss, but 4mg/kg 2x/day did.(110) Some researchers believe that the rat model may closely approximate what happens in humans, while others believe that the rodent may be even more sensitive to the neurotoxicity than humans.(111)

    The inhibition of serotonin synthesis, prevention of proper storage of serotonin into presynaptic vesicles and inefficient transport of serotonin in and out of the synapse due to hyper-activation of the SERT consumes large amounts of ATP. Energy-wastage from this increase of neuronal activity depletes brain glycogen stores that provide glucose for metabolic energy. When the energy-dependent mechanisms for maintaining neuronal integrity are no longer properly fueled, damage and degeneration occurs. (112)

    D. Estimating a level of human neurotoxicity for MDMA

    Due to biochemical individuality it is impossible to determine a safe dosage of MDMA. Likewise, a dose that reproducibly causes human neurotoxicity (structural/functional damage) has not been established. Currently there is a debate as to whether high dose and frequency users of MDMA suffer neurotoxic and permanent changes in their 5HT systems, or whether there is an adaptive process occurring. Currently there are no available methods directly evaluating the status of serotonin neurons in living humans. Studies of MDMA’s neurotoxic potential in humans rely on indirect methods. They include measurements of 5-HIAA in cerebrospinal fluid and neuroendocrine challenge techniques. To date, these studies have been conducted in uncontrolled settings, have been flawed in design and produced conflicting results. (113-116)

    Two promising methods for evaluating the status of serotonergic systems in living humans are imaging techniques such as positron emission tomography (PET) and single photon emission computed tomography (SPECT). There is one PET study purported to show MDMA brain damage that was published in the Lancet in 1998. (117) The results of this study may only be showing an adaptive response of up-and-down regulation of serotonin transporters in a small population of ‘heavy’ MDMA users who had ingested MDMA between 70 and 400 times, over a 4 to 5 year period, and at dosages estimated between 150 to 1250 mg.

    Nevertheless, neurotoxicity has been investigated extensively in animal species and is dose and frequency related. When these data were extrapolated to humans, it was discovered that doses of MDMA that produce neurotoxic effects in non-human primates may overlap with the recreational doses used by some people when differences in body mass and surface area are taken into account. This interspecies scaling model has been challenged by Drs Grob and Vollenweider.

    Dr. Leon van Aerts calculated from animal research that a human dose of 4 mg of MDMA for each kg of body weight could cause nerve terminal degeneration. When a total dose of 10 mg of MDMA for each kg of body is taken in a period of 24 hours, axonal degeneration could be expected. (118-123)

    If an average dose of MDMA contains 100 mg of MDMA per tablet, based on Dr van Aert’s estimates, a 154 lb (about 70 kg) human would need to take about 3 tablets of MDMA to produce nerve terminal degeneration and 7 tablets to cause axon degeneration. We have heard frequent reports of young, naïve XTC users consuming 6-8 tablets during the course of an evening or weekend.

    These toxicity levels for humans are animal-based estimates. The extrapolation from animal data to humans may not be reliable. Some experts believe that even a single dose of 100-125mg MDMA may produce damage. Permanent MDMA related damage from normally used dosages has not been conclusively proven in humans at this time but evidence is accumulating that there are structural and functional changes in the 5HT system. To date there have been no controlled studies showing whether proper nutritional and pharmacological intervention may assist in the recovery of the 5HT system (or whether this is even desirable).

    IV. PROTECTIVE COUNTERMEASURES

    The potential adverse effects of MDMA can be diminished by protective countermeasures.

    A. Antioxidants that deactivate MDMA-generated toxic oxygen species

    MDMA is a catecholamine and by its nature (structure) a pro-oxidant. Even a low dose of 120mg MDMA will increase free radical production and oxidative stress. Our research has shown that even a low dose of MDMA produces a sharp rise in free radicals, as measured by a urinary MDA-TBARS test. Therefore, anyone that is considering using MDMA must bolster the body’s endogenous antioxidant shield and to increase circulating antioxidants. MDMA-induced neurotoxicity involves a wide range of free radicals; including superoxide, hydroxyl radicals and peroxynitrite. Therefore it is essential to supply brain penetrating antioxidants (and their cofactors) that neutralize each type of radical. (124-126)

    The theory of MDMA neuroprotection is simple. Neurotoxicity is directly related to increased oxidative stress. Therefore if oxidative stress can be blocked, so can the neurotoxicity.

    1. Glutathione peroxidase and selenium

    Glutathione peroxidase is a front line enzyme that protects against oxidative stress in the nervous system. It works together with SOD and catalase in a tight knit defense system. GSH-peroxidase reduces hydrogen peroxide to water. Hydrogen peroxide levels increase due to DA and MDMA metabolism. The activity of glutathione peroxidase is mediated by the availability of the mineral selenium. Selenium is incorporated into four sites within the enzyme.

    Supplementation of organic selenium as selenomethionine significantly increases blood and tissue levels of selenium and increases the activity of glutathione peroxidase in human subjects. Vitamin B6 is a necessary co-factor for the selenomethionine to be incorporated into glutathione peroxidase. Selenium protects neurons against methamphetamine-induced dopaminergic neurotoxicity also as a result of increased free radical activity. (127-131)

    Daily Dosage Range: 100-200 mcg of selenium a day.

    Acute Dosage: up to 1000mcg.

    2. N-Acetylcysteine (NAC)

    N-Acetylcysteine (NAC) is a sulfhydryl amino acid that has several characteristics making it a valuable neuroprotective antioxidant. It scavenges the hydroxyl radical, increases the synthesis of reduced glutathione (and glutathione peroxidase) and diminishes the production of hydrogen peroxide.

    NAC has been used to treat neurodegenerative disorders in which free radical mechanisms contribute to their pathology. NAC treatments of myoclonus, epilepsy, Friedreich’s ataxia, neuronal apoptosis, amyotrophic lateral sclerosis and other neurodegenerative disorders produced symptomatic improvements and lowered indexes of free radical pathology. (132-137)

    During the metabolism of MDMA it is first converted to HHMA (which increases superoxide production) and then reacts (via the semi quinone) with GSH or NAC forming thiol conjugates. These conjugates are believed to contribute to MDMA neurotoxicity through increasing oxidative stress and further metabolism to more neurotoxic metabolites.

    See: Nutraceutical and Pharmaceutical Approach to Harm Reduction for details.

    Since NAC is one of the best ways to boost GSH, but may also contribute to NT, it is important not to use NAC for 2-3 days prior to MDMA, and to resume it 2-3 days after use, when free radical levels have returned to normal.

    Dosage Range: 300-1500 mg of NAC a day.

    3. Ascorbic Acid

    Ascorbic acid is a water soluble antioxidant which is distributed throughout the tissues of the body and is concentrated in the central nervous system. Approximately 80% of the total body ascorbate load is found in the brain and specifically within nerve terminals. Ascorbic acid is an important neuroprotective antioxidant that directly scavenges hydroxyl and peroxyl radicals as well as superoxide radicals and singlet oxygen.

    Two studies reported that large dosages of vitamin C (as injectable sodium ascorbate) blocked neurotoxicity in rats. If one takes into account the increased clearance and other pharmacokinetic parameters that change due to the lower body weight of the rat compared with humans, a quantity of 2 grams of vitamin C may protect users of MDMA from oxidative stress. (138-142)

    Dosage Range: 1-2 grams of vitamin C a day.

    Acute dosage: Up to 10g (in the form of calcium ascorbate to minimize

    diarrhea) during MDMA usage. .

    While the normal (baseline) saturation dose of Ascorbate is 250mg/day, much higher levels can be utilzed when the system is under acute oxidative attack. It should be taken with other antioxidants to keep it in a reduced form.

    4. Melatonin

    Melatonin is a powerful endogenous hydroxyl radical scavenger. Additionally, it stimulates mRNA levels for superoxide dismutase and the activities of the antioxidant enzymes glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase, thereby increasing its antioxidative capacity. Melatonin has attenuated methamphetamine-induced toxic effects on dopamine and serotonin terminals in mouse brain due to free radical activity.There are many similarities between MDMA and methamphetamine induced neurotoxicity.

    Melatonin is synthesized at night in the pineal gland from serotonin. The depleting actions of MDMA on serotonin levels can diminish the formation of melatonin and its neuroprotective antioxidant actions on serotonin neurons. Depressed levels of melatonin that produce sleep disturbances can be increased with melatonin supplements and by ingesting serotonin’s direct precursor, 5-hydroxytryptophan. (142-144)

    Dosage Range: 0.5 - 3 mg of melatonin a day.

    Acute dosage: up to12 mg during oxidative stress or to restore natural circadian rhythms.

    6. Alpha Lipoic Acid/R-Lipoic Acid

    The most relevant study for human MDMA users is the study by Aguille who showed that a massive injection of lipoate into a rat blocked MDMA neurotoxicity. (145)

    An equivalent dose with known human PK can be achieved orally at 700-1000mg. An oral solution of lipoate increases plasma concentrations four fold over solid dosage forms.

    The experiment was believed to demonstrate the free radical mechanism for neurotoxicity, but lipoate also serves several other roles that may enhance neuroprotection. Lipoate induces two phase two detoxification enzymes; GST, the enzyme responsible for the conjugation of HHMA to GSH and NQO1 which reduces the HHMA semiquinone(146). Lipoate forms a sulphide bond with hepatic GSH, preventing oxidation and preserving the GSH:GSSH ratio (Reduced glutathione /oxidized glutathione which maintains the cellular redox status and prevents activation of redox sensitive gene transcription factors), causing an efflux of the protective conjugate into the biliary duct.(147) This efflux removes hepatic GSH and prevents it from binding covalently to HHMA. The thiol conjugates of GSH and HHMA are implicated in the neurotoxicity (148). Therefore, it is necessary to maintain both high plasma levels of lipoate (to insure brain penetration) and liver levels (149). Lipoate has a substantial first pass metabolism and bioavailability of ~30%. The first pass is stereospecific with SLA accumulating preferentially (150). Therefore, a spiked ratio of RLA/SLA can cause a substantial increase in RLA plasma levels while allowing SLA and metabolites to react with GSH and cause its biliary efflux. The conjugation reaction is not stereospecific. This allows protection of brain and organ mitochondrial enzymes, which utilize only the R form of lipoic acid. (151) A small amount of SLA non-enzymatically catalyzes the reduction of RLA to dihydrolipoic acid [DHLA](152). RLA is known to be neuroprotective of the DA system and accumulates in the brain over several days bound to the amino acid lysine (153-154). RLA should be used daily in high doses to replenish previously depleted GSH, and prevent further oxidative damage. The formation of toxic conjugates also argues against supplemental GSH precursors like NAC, immediately prior or concurrent with MDMA. Supplemental NAC should be discontinued several days prior to MDMA exposure and resumed 36 hours after MDMA. The concentration of hepatic GSH is less important than the amount of GST, and HHMA semiquinone for conjugation reactions. Lipoate has a short plasma half life and so the timing of administration must be adjusted to coincide with the metabolism of MDMA. This is best accomplished by taking lipoic acid ½ hour prior to concurrently with MDMA and then every few hours afterwards until free radical levels return to normal.

    B. Nutraceutical Neuroprotective Substances

    1. 2-AEP for membrane stability

    2-AEP (2-aminoethanol phosphate, aka Calcium AEP, colamine phosphate) is an essential factor for maintaining the integrity of the cellular membranes of neurons. When the salts of 2-AEP are introduced into the bloodstream they are directed to the cell membrane and integrated into the cell membrane predominantly at the entry spots of the so-called "free lipid pore." It binds fatty acids preceding and following the peptide chains of the cell membrane structure.

    Studies conducted over the last 30 years have shown that 2-AEP has important actions that maintain cell membrane integrity and protect cells from degeneration. 2-AEP performs the following actions:

    · Facilitates transport of electrolytes and essential nutrients into cells.

    · Shields and "seals" cell membranes from harmful agents.

    · Maintains neurotransmission, necessary for the electrochemical communication between cells.

    · Binds calcium and other minerals to cell membranes to serve as "electrical condensers"; essential for cellular regulation.

    · Maintains the bioenergetic cell potential and helps maintain cell receptor sensitivity. .

    In medical clinics worldwide, 2-AEP has been effective in the treatment of various neurodegenerative disorders. This list includes multiple sclerosis (MS) and other sclerotic disorders including amyotrophic lateral sclerosis (ALS) and progressive systemic sclerosis (155-162).

    2-AEP’s regulation of the transmembrane ion exchange, increasing neuronal conductivity, increasing neurotransmissions and preventing cytotoxic destruction of the lipid layer of the membranes of neurons makes 2-AEP a useful neuroprotective supplement for the user of MDMA. 2-AEP may prove useful at repairing the impaired serotonergic neurotransmissions and increasing the diminished sensitivity of serotonin receptors.

    Dosage Range: 1–2 grams of 2-AEP/ day.

    2. 5-Hydroxytryptophan for increasing and replenishing serotonin

    5-hydroxytryptophan (5-HTP) is the direct precursor of serotonin. 5-HTP readily enters the brain where it is readily converted into serotonin. The conversion process requires vitamin B-6 and the enzyme L-aromatic amino acid decarboxylase. 5-HTP does not require the enzyme tryptophan hydroxylase for conversion into serotonin. Tryptophan hydroxylase is significantly reduced for an extended period of time by MDMA usage.

    Research has proven that administering 5-HTP to rats increases the MDMA-induced release of serotonin and dopamine. 5-HTP increases serotonin synthesis and stored levels in the neuron terminal in an energy-efficient manner. This data is consistent with the concept that MDMA increases the extracellular concentration of serotonin by facilitating carrier-mediated serotonin release (CMSR). Since CMSR and nerve terminal storage are increased by stimulating the synthesis of serotonin with 5-HTP, a greater level of psychoactivity with fewer adverse effects can result from the same dosage. It may also be possible to create too much 5HT and induce serotonin syndrome.

    An extensive amount of research has found that 5-hydroxytrptophan relieves a variety of symptoms that match those reported by MDMA users and individuals with low serotonin functions. 5-HTP may be necessary for increasing serotonin activity and preventing the compromise of self-protective mechanisms. (163-170)

    Potential benefits of 5-hydroxytrytophan for MDMA users:

    1) Maintains the entactogenic, empathogenic and sensory enhancing effects of MDMA in regular users of MDMA.

    2) Counteracts MDMA’s serotonin-reducing actions that may produce a serotonin deficiency syndrome.

    3) Compensates for decreased long-term reduction in the enzyme tryptophan hydroxylase caused by MDMA and replenishes depleted levels of serotonin in axon terminals.

    4) Prolongs the entactogenic, empathogenic and sensory enhancing effects of MDMA and compensates for the depleted feelings when coming down from MDMA by providing additional serotonin substrate.

    5) Diminishes the behavioral psychological, cognitive and functional impairments that are associated with low serotonin functions after ‘coming down’ from MDMA.

    6) Promotes the normal sleep cycle that is necessary to restore normal brain chemistry after using MDMA

    7) Decreases the potential neurotoxic action of MDMA by facilitating binding of serotonin in place of toxic metabolites of MDMA in receptor sites on neurons.

    8) Increases serotonin synthesis, storage and efficient transport without wasting high amounts of energy that contributes towards neurotoxicity.

    9) Reduces the development of tolerance to and dependence upon MDMA.

    10) Decreases recovery time and withdrawal from MDMA

    Dosage range: 50-100 mg of 5-hydroxytryptophan a day.

    Acute dose: 100-300mg

    4. Vinpocetine

    Vinpocetine is a derivative from the Periwinkle plant that safely and effectively restores failing neuronal energy. Vinpocetine functions as a cerebral metabolic enhancer and cerebral vasodilator. It enhances oxygen and glucose uptake from blood by brain neurons and increases neuronal ATP bio-energy production, even under hypoxic (low oxygen) conditions. Vinpocetine enhances both glycolytic and oxidative reactions of glucose breakdown for a higher level of brain energy production. (171-180)

    Dosage range: 5 -10 mg of Vinpocetine a day.

    5. Idebenone and CoQ10

    Idebenone (IDB) is a synthetic analog of coenzyme Q10, an important member of the electron transport chain within mitochondria that creates ATP for metabolic energy. Idebenone is a cerebral stimulant that increases brain energy levels. Human and animal studies have demonstrated that IDB enhances serotonin production, even under conditions of a low tryptophan diet and in patients with cerebrovascular dementia. IDB is also a powerful antioxidant that is 30 to 100 times more effective than vitamin E as a free radical quencher within the brain cells. (181-186)

    IDB Dosage range: 45-180 mg/ day. CoQ10: 100-1200mg/day

    5. Ginkgo Biloba Extract

    Ginkgo Biloba extract has membrane-stabilizing and free radical scavenging actions that prevent neuronal disturbances. Ginkgo increases the production of brain energy by increasing cerebral circulation, improving mitochondrial respiration, enhancing membrane dynamics and improving oxygen utilization. It also increases the cellular uptake of glucose oxygen glucose that restores aerobic glycolysis. (187-197)

    Dosage range: 60-120 mg standardized to 24 % Ginkgo flavone glycosides extract three times/day.

    C. Pharmaceutical Neuroprotective Substances

    1. Hydergine and Sermion

    Hydergine and Sermion are derivatives of ergot that are structurally related to the hallucinogenic drug LSD. Hydergine and Sermion increase stores of the energy molecule, adenosine triphosphate (ATP), stabilizes the intracellular messenger molecule cyclic adenosine monophosphate (cAMP) content of nerve cells, improves synaptic connections, improves utilization of glucose in the brain and enhances cerebral microcirculation. Hydergine and Sermion operate as antioxidants to protect neurons from free radical damage. (198-202)

    Dosage range: 3-9 mg of sublingual Hydergine a day. Sermion: 5mg- 30mg/day.

    2. Piracetam

    Piracetam is a powerful cognitive enhancer that stimulates glucose metabolism, increases ATP turnover, improves oxygen utilization, increases cholinergic and dopaminergic activity and enhances neural protection against toxic materials. There are numerous anecdotal reports that Piracetam increases the effects of amphetamines and MDMA. (203-207)

    Dosage range: 2400-4800 mg of Piracetam/ day.

    The newer "racetams", i.e.; Pramiracetam, Aniracetam, and Oxiracetam have not been as extensively explored in this capacity but anecdotal reports suggest that at least Pramiracetam attenuate short term memory loss associated with MDMA usage.

    3. L-Deprenyl and Rasagiline

    L-Deprenyl (DPR) protects the substantia nigra in the brain and dopaminergic nervous system against degeneration. Deprenyl inhibits the metabolism of dopamine, lowering levels of hydrogen peroxide and reducing oxidative stress. In quantities under 15 mg, Deprenyl inhibits monoamine oxidase B (MAO-B) selectively and does not cause a rise in blood pressure. Studies have shown that L-Deprenyl protects against MDMA- induced lipid peroxidation and long-term serotonergic deficits. Dr. Nichols recently reported that >40 and <63% of MAO-B must be inhibited to attenuate MDMA neurotoxicity. It has been reported that a 10-15mg dose of Deprenyl inhibits up to 90% of MAO-B within 3 hours in humans. Several drug related web sites report that Deprenyl/MDMA is a dangerous combination. (208-215) There are no known reports of adverse reactions using the combination and the benefits may substantially outweigh the risks. Deprenyl also stimulates NGF and acts as a Catecholamine Activity Enhancer (CAE) and may even rescue dying neurons by interfering with apoptotic mechanisms.

    Rasagiline will be marketed next year by Teva Pharmaceuticals for Parkinson’s disease and has outperformed DPR in most head to head studies, including cell rescue. It has not been tested with MDMA, but its pluripotent mechanisms suggest that it will be even more neuroprotective than DPR. Since 5HT terminal degeneration follows a known time course, Rasagiline should be tested for its ability to reverse damage.

    Dosage range: 1-5 mg of deprenyl/day

    Acute Dosage: 5-15mg maximum

    4. Bromocryptine

    Bromocryptine is a D2 agonist utilized in treatment of Parkinson’s disease. It is an excellent scavenger of hydroxyl radicals and has been demonstrated to block methamphetamine neurotoxicity. It is more neuroprotective than Deprenyl in the hippocampus and may provide protection of lipid membranes by inhibiting hydroxyl radical and suppressing DA turnover. (216)

    Dosage range: 2.5-10 mg/day

    5. SSRIs for blocking MDMA neurotoxicity and reduce MDMA’s psychoactivity

    Researchers have discovered that selective serotonin re-uptake inhibitors (SSRIs) like fluoxetine (Prozac), fluvoxamine (Luvox), citalopram (Celexa), paroxetine (Paxil), sertraline (Zoloft) block the neurotoxicity of MDMA in animals. Prozac has been used most frequently in this capacity. The mechanism of protection involves blocking the SERT so that toxic free radicals and/or metabolites are prevented from entering the terminal. Recently it was also demonstrated that SSRI’s protect enzyme sulfhydryl groups from being oxidized, including those of tryptophan hydroxylase. (217)

    Unlike the SSRI drugs, MDMA enters the neuron through the reuptake transporter and causes a release of serotonin. The released serotonin then enters the synaptic cleft through the serotonin transporter. It is thought that the efflux of serotonin into the synaptic cleft, and its subsequent action on pre and post- synaptic binding is primary to MDMA's psychoactivity.

    Taking an SSRI with MDMA to reduce the risk of adverse reactions has been found to lower the psychoactive effects of MDMA. This is believed to occur because the SSRIs attenuate the MDMA-induced release of serotonin and dopamine. It has been reported from survey data that a majority of MDMA users who simultaneously use Prozac and other SSRIs have either an absent or diminished response to MDMA. (218-220)

    For the user of MDMA, concurrent use of SSRIs may be self-defeating. A higher dosage of MDMA is required to experience the same level of psychoactivity. Higher dosages increase energy wasting and the likelihood of adverse effects from MDMA. SSRIs produce their own side effects. They can compromise libido and flatten emotions. For example, 34% of Prozac users reported a loss of libido and diminished sexual response. (221) These side effects generally occur after a steady state plasma level is achieved which requires 2-3 weeks of continuous usage. It is most likely not problematic in the short term. SSRI’s may be taken acutely 3-6 hours after MDMA in combination with antioxidants. The subsequent administration of an SSRI was neuroprotective in animals and did not interfere with the desired entactogenesis.

    For a discussion of the interaction of SSRI’s with the CYP450 system, see:

    The Nutriceutical and Pharmaceutical Approach to Harm Reduction.

    Acute dose: 20-60 mg Prozac (fluoxetine)

    Warning: Many people have used 20mg Prozac following MDMA with no adverse reaction. The higher dose suggested here is necessary to produce the equivalent of a steady state plasma level which normally requires 2-3 weeks of 2x 20mg doses/day. It may also increase the probability of serotonin syndrome. Dr Ricaurte suggests that SSRI’s (at least in high doses, concurrent with high doses of methamphetamine) may shift the stress away from the 5HT system into the DA system. Therefore it is essential to take substances that protect the DA system as well. Prozac and Deprenyl are also generally considered a dangerous combination, and should be avoided. We have heard reports of young XTC users using SJW is equivalent to an SSRI, in terms of neuroprotection. There are wide variations in hyperforin contents between brands of standardized St John’s Wort. SJW must be used for several weeks to block 5HT uptake. This material may also interact with the CYP 2D6 enzyme and increase blood levels of MDMA.

    See the Nutraceutical and Pharmaceutical Approach to Harm Reduction for details.

    D. Preventing hyperthermia and oxidative stress damage from MDMA

    Hyperthermia (HT) significantly enhances the generation of free radicals from MDMA. HT increases the potential for neurotoxicity and contributes to the MDMA-induced decrease in tryptophan hydroxylase activity causing serotonergic underfunctioning. (222-228)

    High ambient temperatures, crowding, alcohol/multi-drug use, inadequate fluid and electrolyte replacement and elevated physical activity levels of MDMA users exacerbate the problems of hyperthermia. These factors raise body temperature and increase the risk of oxidative stress damage. The resulting hyperthermic state may lead to dehydration and place stress on liver and renal functions. Hyperthermia may also be a contributing factor to a number of reported deaths in human recreational MDMA users.

    Preventing overheating and high doses of antioxidants are essential measures for minimizing the risk of a neurotoxic reaction to MDMA. This can be accomplished by reducing the ambient temperature, wearing light clothing and drinking enough water during each hour of MDMA use for rehydration. Unfortunately, many users of MDMA frequent crowded, hot dance clubs and dance strenuously for hours without a regard for replacing fluids and overheating their bodies. Dehydration is worsened by concomitant consumption of alcohol.

    E. Improving neural bioenergetics to prevent failure of self-protective mechanisms

    Dr. Heuther and his colleagues in Germany propose that the metabolism of MDMA profoundly wastes energy. This creates a brain energy shortage and failure of self-protecting mechanism in neurons. When a certain critical threshold of these self-protecting mechanisms is exceeded, degeneration of serotonin neurons occurs from toxic and reactive free radical molecules.

    Recognition of the role of neural energy exhaustion suggests that the long term neurotoxic damage from MDMA can be decreased by treatments that improve global energy metabolism in the brain. Listed under section V. B and C are nootropic agents to improve the bioenergetics in the brain and nervous system. (229). Heavy MDMA users will require a longer recovery period to replenish depleted energy substrates and glycogen stores.

    F. Establishing a safe MDMA dosage regimen?

    Is it possible to establish a safe dosage of MDMA? At this time and with our current state of knowledge it is impossible to establish a safe dosage of MDMA for a given individual. It is our best advice, based on current research to AVOID USING MDMA. This is the safest approach. If you decide to ignore this advice, then it is absolutely essential to take antioxidants in order to reduce oxidative stress and possible neurotoxicity. It is also essential to minimize use. Most pro-MDMA elders believe that it is best to limit usage to 2-3/year maximum. As discussed earlier and in more detail in The Nutriceutical and Pharmaceutical Approach to Harm Reduction there is a sharp and sustained rise in biomarkers for oxidative stress even after a low 120mg dose of MDMA.

    This can be demonstrated by use of the Rad Test.

    A pioneering and proven concept is taking small frequent doses of MDMA that cause up-regulation and morphologically reorganize neuronal structures to a neurochemistry for lasting well being and happiness. In other words, endeavor to reprogram the brain over time to permanently produce the benefits and ‘feelings’ of MDMA. An experimental dosage regimen for this could be 0.25-0.45 mg of MDMA for each pound of body weight taken every other day or several times a week(230).

    VI. BEHAVIORAL AND NEUROPSYCHIATRIC EFFECTS OF MDMA

    Even if no structural abnormalities are produced by human use of MDMA, the neurochemical and behavioral changes induced by recreational misuse of MDMA due to alterations in brain chemistry are of concern. Disruptions in serotonin synthesis may produce psychological side effects ranging from post- MDMA burnout, to the psychiatric effects that have been observed in some MDMA users.

    A. Adverse behavioral and psychological effects

    Various psychological disorders and behavioral complications have been linked with the use of MDMA. Heavy weekend users may have midweek problems such as low mood and irritability and may develop a dependency on MDMA. Studies have reported different degrees and types of impairment in cognition and memory associated with the use of MDMA. Critics claim all of these studies are flawed in their design. Furthermore, none of these studies tested a person’s memory before and after their MDMA use to determine whether or not it became worse. Preexisting differences between the test subjects and polydrug use could produce the results attributed to MDMA. (231-238)

    Another study presented data from 500 people who self-reported immediate and long-term effects of MDMA. Most of the subjects had used MDMA for years. The study reported high levels of adverse psychological effects.

    A. Immediate effects : paranoia, 20%; anxiety 16%, depression 12% .

    B. Long-term/recurring effects: depersonalization 54%; insomnia 38%; depression 38%.

    There are many published reports of other neuropsychiatric complications associated with the use of MDMA. They include panic attacks, extreme disorientation, psychosis, flashbacks, catatonic stupor, delusions and suicidal ideations. (239-245)

    Few of these severe neuropsychiatric complications have ever been attributed to the controlled use of MDMA in the psychotherapy setting when administered biweekly in a dosage range of 125-250 mg and in clinical experiments with dosages up to 2.5 mg / kg of body weight. Studies have not demonstrated a causal relationship between MDMA and these neuropsychiatric manifestations in normal individuals. However, every legal and illegal recreational psychotropic drug may induce transient neuropsychiatric effects that manifest themselves as behavioral, emotional and cognitive disturbances. Every drug user should be aware of this possibility.

    Reviews of the reported immediate and long term effects of recreational MDMA overuse mirror the symptoms associated with serotonin deficiency. Increasing levels of serotonin to normalize serotonergic functioning has effectively treated many of these problems.

    There are two practical methods to increase serotonin activity:

    (1) Increase the natural production of serotonin by ingesting 5-HTP

    (2) Increase serotonin activity with SSRIs by interfering with the natural process of serotonin reuptake. Unfortunately, when the activity of the enzyme tryptophan hydroxylase is diminished by MDMA, serotonin and Melatonin synthesis diminishes and the actions of SSRIs may not be as effective. The SSRIs have numerous potential side effects including a blunted emotional response to normally pleasurable stimuli.

    B. Beneficial behavioral and psychological effects

    In a clinical environment, MDMA has produced a high success rate in helping treat patients with neurotic and psycho reactive disorders. MDMA has been of benefit in the treatment of physical pain and emotional stress associated with severe medical illness, post-traumatic stress disorders, depression, phobias, addictions, psychosomatic disorders and relationship (marital) problems. MDMA helps patients overcome defenses, improves the ability to communicate and enables the therapist to confront the patients’ problems by reducing anxieties and fears. (246-248)

    In a non-clinical setting of recreational use, the most universal psychological effect that MDMA users report is a positive mood state. This effect was reported 94% of the time in a 1994 study. Other positive psychological effects included a sense of euphoria, elevated self-esteem, feelings of spirituality and closeness to others, open mindedness, empathy and need for intimacy. (249)

    The late Nicholas Saunders, a former director of the Institute for Social Inventions, surveyed the long-term effects of MDMA, showing that most users rated themselves as having become more caring, more in touch with their spiritual nature, closer to nature, having increased happiness and self-esteem. (250)

    The recreational user often turns to MDMA to experience the effects of Entactogenesis (a generalized feeling that all is right and good with the world), Empathogenesis (feeling of emotional closeness to others and a breakdown of personal communication barriers) and sensory enhancements. MDMA helps to reduce anxiety and takes the edge off of life.

    The deep sense of love, trust and empathy makes MDMA the ‘penicillin of the soul’. But like an antibiotic, when MDMA is overused, the positive effects diminish or vanish. (251)

    High doses and high frequency may hasten the development of serotonergic underfunctioning that blocks the Entactogenesis, Empathogenesis and the sensory enhancements from MDMA. As a consequence, the initial benefits and feelings from MDMA turn into a memory.

    Unfortunately, it is common for a heavy recreational user of MDMA to take 500-1000 mg of MDMA over the course of a weekend. These dosages could account for the reports of severe confusion, high anxiety, depression, panic attacks, depersonalization, hallucinations, flashbacks, paranoia and psychosis as well as a variety of adverse physical reactions (including death) that have been attributed to MDMA. This is especially true when the MDMA is contaminated and taken with other psychoactive drugs and /or the user has pre-existing mental problems. Polydrug use is a very common phenomenon among MDMA users.

    In summary, the long term (high dose and frequency) recreational use of MDMA may produce permanent changes in cognitive and psychological processes that correlate with the level of use and serotonergic functions. The psychological effects may be beneficial when MDMA is taken in a controlled dosage regimen. Overuse and abuse of MDMA increases the occurrence of adverse psychological reactions and neurotoxicity.

    C. Withdrawal, tolerance and dependence to MDMA

    Withdrawal

    Although not affecting everyone, many people report that withdrawal ("come down" from single or repeated doses over a short time) from MDMA roughly follows a six to seven day cycle. The day after taking MDMA, most users (if they had enough sleep and had not combined it with other drugs), feel an "after glow" of elevated spirits. On the second and third days, low moods, lethargy, unsociability, irritability and cognitive impairment are commonly experienced. This continues into the fourth day. With the 5th day there is a relative recovery of mood and normal functioning. The cycle frequently repeats itself with MDMA reuse on the 6th or 7th day. Insomnia for several days after using MDMA is a common experience.

    In the average user of MDMA, withdrawal symptoms develop during a period of neurochemical depletion that follows MDMA acute effects. There is a measurable but transient post-MDMA serotonin dip that may represent an adaptive response to the drug.

    When the chronic high dosage user of MDMA comes down, they may experience more severe withdrawal reactions. This includes extreme fatigue and excessive sleeping followed by anxiety insomnia and depression. Some of their symptoms appear more like the withdrawal symptoms to amphetamines. There may be residual effects of lethargy, depression, irritability and other impairments from serotonergic underfunctioning. (252-253)

    Tolerance

    Tolerance to MDMA develops with repeated use, which may lead to escalating dosages. This appears to be a result of neurochemical and psychological changes. The effects of MDMA increasingly begin to resemble those of amphetamines. The empathogenic "love feelings" and entactogenic "touching within feelings" from MDMA rapidly decreases. As compensation, the MDMA user frequently increases the dosage levels in a vain attempt to recover the state which was experienced initially. As mentioned above this may be due to down regulation rather than tolerance in the sense used in opiate addiction.(254-255)

    Dependence

    Dependence to MMDA may develop with repeated use. MDMA has similar effects on the dopamine pleasure centers of the brain as the drugs of addiction, cocaine and amphetamines. Consequentially, regular MDMA users may find themselves relying upon MDMA to stimulate pleasure and reward circuits in their brains.

    This mechanism has been demonstrated in animal research. Impaired serotonergic functions have been linked to increased self- administration of amphetamine and cocaine because of the interaction between serotonergic systems and dopamine pleasure centers in the brain. (256-259)

    An underlying common chemical basis for withdrawal effects, tolerance and dependence

    to MDMA is an under-functioning of serotonergic nerves due to compensatory alterations (down regulation) in serotonin transmissions and receptor cell sensitivity as a result of chronic MDMA usage. Normalizing the serotonergic system of the brain by replenishing depleted levels of the neurotransmitter serotonin, improving serotonin receptor cell sensitivity, raising levels of dopamine (if necessary) to restore neurotransmitter balance and improving dopamine cell receptor sensitivity (if necessary) helps to counteract the neurochemical basis of each of these problems. Recommendations to counteract withdrawal effects, tolerance and dependence to MDMA include:

    Taper down MDMA dosages and frequency of use or stop using MDMA.

    Taking small dosages of MDMA during the recovery phase consisting of a fraction of the dosage that normally produces up-regulation (0.1-1 mg /kg of body weight) may help some MDMA users.

    Boost underactive serotonergic functioning by taking the precursor to serotonin, 5HTP (150- 300 mg) after midday.

    Take .75 - 3 mg of the hormone melatonin at bedtime for sleep and rhythmic balance.

    Boost underactive catecholamine activity by increasing the synthesis of the neurotransmitter dopamine. Ingest 0.5 –1.5 grams of the amino acids L-tyrosine (or N-acetyl tyrosine) and L-phenylalanine early in the day on an empty stomach. These amino acids are precursors to the catecholamine neurotransmitters. A standardized extract of the herb Mucuna pruriens containing 15% l-dopa, the immediate precursor of dopamine, may produce a significant increase in dopamine levels, but should be taken with high doses of antioxidants to diminish oxidative stress. L-dopa taken days in advance of MDMA and then discontinued prior may up regulate COMT, providing greater neuroprotection.

    Caution: Macuna pruriens should not be taken with MDMA. This will increase the formation of toxic free radical molecules. Macuna pruriens is best taken on the recovery days following the use of MDMA with high doses of antioxidant, and carbidopa.



    Ingest the cell membrane integrity factor 2-AEP to repair damaged neurotransmissions and improve cell receptor sensitivity.

    Extreme MDMA use requires a longer recovery period to replenish depleted energy substrates and glycogen stores for brain energy.

    Eat a healthy diet, take a high-potency multi-nutrient supplement, and get an adequate amount of sleep each night to promote recovery.

    VII. MDMA AND CHRONOBIOLOGICAL DESYNCHRONIZATION

    An effect of MDMA that has been recently addressed in the literature is "chronobiological desynchronization" (260). A wide array of our biological processes and functions are organized and integrated in a time-related manner. Certain chemicals such as GHB and psychotropic drugs, including MDMA have the ability to alter biological rhythms. They alter the activity of the neurotransmitters serotonin and dopamine that are part of the circadian regulatory system. Such agents are known as chronobiotics.

    Chronobiotics can either delay or advance the phase of circadian rhythms. Amphetamines have been shown to lengthen the circadian period.

    Circadian rhythms repeat every 24 hours and coordinate the person with the environment by using environmental cues or zeitgebers ("time givers", for example, the light/dark cycle). Under normal situations, these diverse rhythms usually maintain a distinct phase relationship to each other and rely upon external cues that keep them in synchronized over the course of a day. Problems occur from circadian dyschronism (a.k.a. chronobiological desynchronization) as a result of the loss of regulation of multiple neurochemical and neuroendocrine systems.

    The hypothalamic-pituitary axis (HPA) is the primary site of regulation. The HPA regulates the circadian switching from a daytime energy-generating catecholamine pathway to the nighttime repair and energy-conserving indoleamine pathway every 12 hours.

    A. Effects of chronobiological desynchronization

    Imbalances in both amplitude (hypo-or- hyper secretions) and phase (wrong time for secretions) of dopamine (DA) and serotonin (5HT) can

    (1) Disrupt internal oscillations

    (2) Disorganize temporal organization

    (3) Desynchronize the body’s endogenous biorhythms with the environment

    (4) Create a wide array of psychological problems.

    A disruption in the biological rhythms may produce changes that are similar to age-related functional decline which is a hallmark of the aging process. Listed below are some of the early and later effects of chronobiological desynchronization. (261-267)

    Some early effects of chronobiological desynchronization: fatigue, mental fogginess, disorientation, reduced physical ability, reduced mental acuity and memory loss, off-schedule bowel movements, disturbed eating.

    Some later effects of chronobiological desynchronization: fatigue, insomnia, depression, loss of appetite, constipation or diarrhea, reduced motor coordination and reflex time, lack of sexual desire, headaches, menstrual problems and erectile dysfunction.

    Disturbances of chronobiological desynchronization match the reported disturbances from the recreational misuse of MDMA. This is the result of MDMA’s wasting neural energy resources and altering the activity of serotonin and dopamine that maintain circadian rhythms. Substituted amphetamines, like MDMA, deplete brain glycogen levels and alter sleep patterns. (268-274) Sleep disturbances are a prominent factor in chronobiological de-synchronization.

    Chronobiological de-synchronization is a key feature of serotonin deficiency syndrome.

    In other words, MDMA can create a unique affective disorder comparable to a long lasting ‘jet lag’. Compounding the problem of pharmacological de-synchronization is the "all-night, dance ‘til dawn" lifestyle, (sometimes for several consecutive days), minimal exposure to sunlight and poor diet.

    B. Chronobiotic agents to stay in sync

    Chronobiological de-synchronization from the misuse of MDMA may be brought back to balance by ingesting chronobiotic agents. These agents re- synchronize body/brain rhythms by normalizing catecholamine levels during the active daytime phase and indoleamine levels during the nighttime phase of the circadian cycle. Proper use of these substances may restore dysnchronic biological oscillators into harmony with one another and environmental cues. This may prevent temporal deregulation of the neuroendocrine system and keep it from triggering adverse behavioral, psychological and functional disturbances. (275-279)

    Daytime chronobiotic factors to be taken in the morning:

    L-tryosine & L-phenylalanine: 500-1500 mg of each amino acid (on an empty stomach)

    Vitamin B-6 or pyridoxal 5 –phosphate: 30-60 mg

    St John’s Wort Standardized Extract (.3% Hypericin, 3-5% hyperforin): 300-500 mg

    SAMe 200-1200mg

    Nighttime chronobiotic factors to be taken in the evening:

    5-hydroxytryptophan: 50-300 mg

    Melatonin: 0.5-1.5 mg

    Vitamin B6 or pyridoxal 5-phosphate: 30-60 mg

    St John’s Wort Standardized Extract (.3% hypericin): 300-500 mg

    Caution: St. John’s Wort extracts provide constituents that

    (1) Inhibits MAO type-A (like MDMA) preventing the breakdown of catecholamines, i.e. dopamine and indoleamines, i.e. serotonin

    (2) Improve the signal produced by serotonin after it binds to the cell receptor

    (3) Bind GABA receptors like anti-depressive benzodiazepine drugs.

    Caution when combining, St Johns Wort and MDMA, since SJW may increase blood levels of MDMA by inhibiting the phase 1 CPY2D6 enzyme that metabolizes (via demethylenation) MDMA. Conversel ,this competition for the CYP enzyme may decrease the neurotoxic potential by reducing the formation of thiol adducts of HHMA.

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  2. abinhibitxtra

    abinhibitxtra Newbie

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    Thanks for this great info!
    I am doing a little study on it so this info is welcome.
    Just a little question, can you explain the acute dosage, when to use the acute dosage after or during(?) using mdma and for how long ?
    And when to switch to the normal doses?

    Thanks!

    abinhibitxtra added 1 Minutes and 2 Seconds later...

    Just realized this is a very old topic!
    Sorry to bump it iup, but I think it is still actual.
    I hope the poster is still around to answer:)
     
    Last edited: May 13, 2010
  3. avcpl

    avcpl Silver Member

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    don't apologize for bumping it, I've never seen it before and I'm sure others haven't either! THANKS!
     
  4. mogle42

    mogle42 Newbie

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    kudos on the extremely well written report.

    something to add about the mdma appetite suppresant "myth". though its true mdma wasnt mda was sold and used in the 60s for an appetite supressant. i find this always left out. granted it has little to do with mdma it does clear up the easy confusion of a dropped letter. it would also bring more legitamacy to using mdma and or mda for medical/therapeutic uses.

    simply dispelling the myth and saying no its wrong doesnt help at all. also with neurotoxicity of mda being greater than mdma could also be added to keep up with it being safer.maybe also adding how both mdma and mda was used(tested) and kept on contract.

    i know its kinda pointless coming from a noob like me. especially with how well written the report is. however the mda mdma simple confusion makes alot of "knowledgeable" people feel really stupid and confused when they read that.

    again great job
     
  5. Priapism9

    Priapism9 Silver Member

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    I dont think this was actually written by the original poster but most likely pulled from somewhere, so adding to, and editing might not be an option. Maybe some cliff notes.
     
  6. abinhibitxtra

    abinhibitxtra Newbie

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    You are probably right. Some cliff notes would be nice though.
     
  7. abinhibitxtra

    abinhibitxtra Newbie

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    What I would like to know about the 5-htp use after the use of E is in this report it says, start 3 days after use. Why not start right after use?
    In other parts of this forum and on other websites it is stated that use of 5-htp can start right after one comes down from use.
    What is best to avoid the 'hangover' and midweek blues?
     
  8. alienesseINspace

    alienesseINspace Titanium Member

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    This post answered my question and being on an SSRI and trying to take MDMA. I was wondering what would happen to the sheep I saw on the hill who is on an SSRI who wants to roll again. I also am trying to figure out if I took an "SSRI holiday" [which is NOT in the spirit of harm reduction, just something I'm wondering] how long I'd have to be off the SSRI to benefit from the MDMA.

    Also being down emotionally after MDMA sounds like an SSRI could help...
     
  9. carnagexp

    carnagexp Newbie

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    Hi,
    I am trying to find out as much information as possible relating to the ecstasy manifesto posted.

    I need help badly and have posted a thread here explaining:
    https://drugs-forum.com/forum/showthread.php?p=1132409#post1132409

    Any information from people who have either experienced the same thing or know who wrote the original article would be greatly appreciated.
     
  10. Sarasti

    Sarasti Newbie

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    I'm necromancing this thread to ask the following question, about the "micro"-dosing approach proposed here:

    A pioneering and proven concept is taking small frequent doses of MDMA that cause up-regulation and morphologically reorganize neuronal structures to a neurochemistry for lasting well being and happiness. In other words, endeavor to reprogram the brain over time to permanently produce the benefits and ‘feelings’ of MDMA. An experimental dosage regimen for this could be 0.25-0.45 mg of MDMA for each pound of body weight taken every other day or several times a week(230).

    I absolutely cannot find the referenced paper. I'm a university student with access to most papers... and I've gone as far as contacting an active MAPS psychiatrist about this, but we came up with nothing.

    My main issue is with the dose suggested, because I think it's a mistake. While most of the doses in the article are in mg/kg, this is stated in mg/lbs, which is both silly science wise and inconsistent with all other mentions of doses.

    Anyone have any idea?
     
  11. Mexicantrance

    Mexicantrance Newbie

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    I agree with Sarasti.

    The doses mentirones in the paper are way too high!
     
  12. yngvae2

    yngvae2 Newbie

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    ive consumed about an oz over a year, ive had some serious melotonin and serotonin syndrome because of it 3 times and learned how to avoid it, ive found that getting more sleep and taking 5 htp regularly cycling it, can help keep your health up tremendously.also cycling use of mdma helps a lot too. you can pretty much take it regularly for a month, then off a month and be fine forever , as long as you dont overdo it. and take about 50 % off time during the week.even if you fuck your brain up, it will heal just fine if you go off it for a month or two. as long as you stay off all serotonin releasers during that time period. also if youre feeling like youre having sleep issues, take some melotonin before bed, if you are low on serotonin then you cant produce melotonin and lack of melotonin is responsible for sleep terrors and paralysis caused by overuse as well as trouble sleeping.

    yngvae2 added 1 Minutes and 35 Seconds later...

    also ive noticed that if you have a wife or gf, buy a safe and have them put it in there and dont give you the code, when youre rolling, everythings a good idea and its easy to overdo it because youre not thinking clearly in that state, having someone sober or not rolling or drunk with higher inhibitions to distribute it to you is the best thing for your health! trust me!

    yngvae2 added 1 Minutes and 58 Seconds later...

    oh and another thing make sure your mdma is pure, pure mdma is relatively safe, if not abused, but ive noticed the bath salts and other upperish stuff in there seems to be more toxic and cause health issues.so get a few test kits and have experienced users like myself test it for you. a real pro will have no problem discerning if its pure or not.

    yngvae2 added 2 Minutes and 25 Seconds later...

    ive also heard from a study if you take welbutrin a few hours after ingestion, it will block all the neurotoxicity caused by mdma, but this is adding more drugs into the body which may have its own health issues , thus why I never considered it,
     
    Last edited: Dec 27, 2014