Just like to say very nice forum you have here GOD.
I've never tried piracetam and there are no claims for it's use in studies before or after mdma that I'm aware of. I can only state my claims for the use of antioxidants (and there are 2 studies to back this up, one with Vitamin C, and the other with alpha-lipoic acid). The claims with piracetam are solely on the basis of reading user reports on the web, like this one for instance from Xorkoth (senior moderator at another site). I surely don't believe everything I read on the web, and like to rely more on scienctific studies when they are available or personal expierence. The smart drugs books I've owned for a long time and they can still be found used for a few dollars each. The book cites "memory improvements" when combined with choline, but no improvements before or after drug use, somebody else may have stated that they noticed improvements before or after drug use with it (The Ferret). But based on reading numerous experience reports, it seems that it can play a healthy role. It's also important to note (as the books state) that smart drugs do not work for all people, and there is a "sweet spot" with smart drugs that has to be personally found, as when too much of a smart drug is taken, it can have the opposite effect or no effect at all. It's a field of research that still has to be taken with a grain of salt and personally verified through personal experience over a long period of time with lots of experimentation.
Xorkoth:
I recently had an MDMA experience after not having had one in years, and I experienced no negative effects or aftereffects whatsoever. This is with a person who previously, even when taking long breaks between, would feel quite depressed, lethargic, and just plain crappy for up to a week after a single dose.
I took 100mg 5-HTP before, during, and after the experience. I took 1g piracetam beforehand, and I feel that this was the biggest factor. I've read numerous reports on Erowid (mostly) and elsewhere where people claim that piracetam before MDMA makes it more gentle, more powerful in emotional effect, and makes it taper off slowly instead of just suddenly ending. It did all of this for me, for sure, and the next day I felt absolutely great, even though I didn't sleep whatsoever.
I've also heard that Prozax in particular, when taken afterwards, helps to protect your brain. Personally, I would recommend piracetam taken beforehand and 5-HTP throughout. The difference that piracetam makes in all psychedelics, actually, is truly amazing.
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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-cool.gif 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
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This said... We can actually take MDMA without any to low neurotoxicity, so anyone reading this can put these supplements on your shopping list and at least pick up vitamin C ester and alpha-lipoic acid and anything else you can afford.
