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> Racetams with NDRIs
ERICURN
post Jun 13, 2013, 02:17 PM
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Looking for some feedback about taking racetams with NDRIs.

The main question is that when I research racetams the thoughts about their exact moa seem to vary from source to source. Some however report that racetams have an agonist effect on NMDA as well have being similar too and having a similar action as GABA.

The moa of NDRIs is pretty self explanatory, hence the name. There is clear evidence that NMDA antagonist slow tolerance to opiates and to some degree NDRIs. Thus one could assume by default that NMDA agonist (racetams) could possibly cause an increased tolerance to NDRIs and actually reduce their effectiveness. Also GABA is released by the brain as an inhibitory substance when Dopamine and Norepi are in high amounts to counter act or balance the effects. If racetams act similar to GABA then that aswell might reduce the effectiveness of NDRIs moa. I recognize this is truncated and could be described in more detail but those familiar with these substances will get the idea. I’m simply looking for some thoughts on combining these 2 substances. Good idea, Bad idea, etc. And as always nothing would be taken with discussion with a doctor first.
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Flex
post Jun 13, 2013, 02:43 PM
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If you want my honest answer, I say mu. It is completely dependent on what NDRI you are taking, and what exactly you mean by effectiveness. What you are not likely to gain from that combo is cognitive health.
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ERICURN
post Jun 13, 2013, 03:08 PM
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What about that combo is anti- cognitive health? And do you mean subjectively as in felt or precieved benifit or objectively as in actually not healthy for the brain or both?
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ERICURN
post Jun 13, 2013, 03:24 PM
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NDRI being spoken about would be extended release MPH. If one has found MPH to be a huge help and has been able to stay on the same dose for a while and wanted to slowly add supplements that would be supportive and aid cognitive ability and health what would you recommend?
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Flex
post Jun 14, 2013, 06:20 AM
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I would recommend you try not taking anything and see what sort of effect your wonder drug is actually having on you. To say that the mechanism of action of NDRIs is understood is a gross misrepresentation of the literature. Anyone who tells you otherwise is 1.) ignorant 2.) not a reliable source of information.

P.S.
I would be happy to challenge anyone who makes said claims with a literature review.

Fast forward to page 10:
http://link.springer.com/chapter/10.1007/7854_2011_144

I am fairly confident nothing has really changes significantly since 2012.

That being said, it would be very irresponsible of me to suggest that anyone should be taking something which is unnecessary and may cause life long changes not only to you, but potentially to your offspring as well.
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ERICURN
post Jun 14, 2013, 07:55 AM
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I recognize there is much about MPH that is not fully understood and that my original post was very truncated and lacking detial. However I think that the overall literature and research into MPH is pretty clear and consistent on its MOA with in the brain. How that MOA improves certain illiness or improves baseline cognitive function is not as fully understood but is still well understood. MPH has been around as an RX for 60+ years and there are studies showing its long term effects. I would not make the same argument for amphetamines because much more comes into play when taking into account the reversal of DAT etc. But I think even they are well understood. I also never claimed MPH to be "a wonder drug" it is however a helpful RX for many people who are in need of it and had a great safety profile when used appropriately especially when an extended release version is used. One is generally able to remain on the same dose long term with much improvement in symptoms. I do respect your willingness to be responsible and not give recommendations about an RX med. I would never recommend others taking or mixing any RX without consultation, work up, and a script from a qualified Dr. I'm just curious about your first post that racetams + NDRIs is anti cognitive health. I'm not trying to be argumentative and am happy to be corrected where wrong I simply want to learn.
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Flex
post Jun 14, 2013, 12:00 PM
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I would argue that the mechanism of action is at best trivially understood. Ephedra has been around for thousands of years, but that does not make it safe or well understood.

"The mechanism of action of ADHD medications is not well-understood (Heal et al. 2011). Most studies have focused on synaptic reuptake or release of neurotransmitters (Swanson and Volkow 2002) but this may be only one mechanism. Administration of methylphenidate in adolescent rats has been reported to upregulate over 700 genes in the striatum"

Unless you know your brain voltage, speed, rhythm and synchrony, there is no way to quantify weather or not you are receiving benefit or doing harm. That said, it is probably safe enough. What effect will it have? Who knows, that is what guinea pigs are for. No one has come close to studying anything remotely similar that I am aware of.
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ERICURN
post Jun 15, 2013, 07:47 PM
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Flex, thanks for the input, I'm new to this site and you seem intelligent and well read so I'm grateful for the dialog. I see what you're saying in your last post and think I misread you at first. I recognize that the overall moa is maybe not well understood. As we make advances neuroscience, neuropharmacology, and over all medical science we are going to probably constantly discover that the moa of many chemicals whether from drugs, supplements, food, or even those inherent within our self are not well understood. When I said MPH was well understood I was speaking specifically to its ability to act as a NDRI. Now I recognize that there is still areas here that are not fully grasped however I do think the overall view within the medical comunity is that MPH does act as an NDRI and that this moa is effective in treating certian conditions. I also think the general concensus is that it is generally safe when used used aappropriately.


"Methylphenidate is commonly used for the treatment of attention-deficit hyperactivity disorder (ADHD). Its efficacy in improving the core symptoms of ADHD, as well as some of the aggressive and oppositional behaviours, is well documented, based on a large volume of research. Methylphenidate has a wide margin of safety and relatively mild adverse effects, most commonly appetite suppression and insomnia. Methylphenidate is a rapidly absorbed medication that, in its d-isomer form, readily penetrates the CNS, particularly the striatum." (Wolraich 'Pharmacokinetic considerations in the treatment of attention-deficit hyperactivity disorder with methylphenidate.')

Either way I have no real desire to debate out all the effects of MPH there are many people who have greatly benefited from it and many who haven't.

However Im still curious as to your first post about combining it with a ractem being unhealthy. Im not saying I even want to take them together. There are many accounts of people who have but as my first post pointed out im really looking for some info on how there moas would interact.
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Flex
post Jun 16, 2013, 05:30 PM
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I did not mean to imply the combo was inherently unhealthy, but rather that MPH is unhealthy. As someone who likely induced psychosis due to stimulant use as a child, I cannot help but raise a red flag when I see something touted as safe when it has fucked so many people up. Honestly it is probably not going to make a particle of a difference if you add piracetam or not. By definition, one should not notice ANYTHING from a nootropic, including cognitive enhancement. One would be able to detect cognitive enhancement at the population level only (research studies). That said, if you actually look at the studies on piracetam, they are complete and utter bullshit for the most part, and thus any claims, including those mentioned below are likely inaccurate bullshit as well.

Here's a little excerpt from a project I was working on that fell through about a year ago:


In 1964, a new compound, piracetam, was synthesized by Romanian chemist/psychologist, Dr. Corneliu E. Giurgea. Giurgea described his new drug, piracetam, as being nootropic. The term "nootropic" come from the Greek words nous, "mind" and trepein, "to move towards". Giurgea established nootropics as a new class of compounds by laying down general guidelines that ought to be met before a substance may claim nootropic status.

Giurgea's suggested that in order for a compound to be considered a nootropic, a compound must facilitate the learning process, or enhance memory by some measurable index. A nootropic should protect the brain from physical or chemical injury, preserving cognitive function even under conditions known to cause impairment such as lack of oxygen, stress, alcohol exposure, etc. Exhibit few side effects and extremely low toxicity, while lacking the pharmacology of typical psychotropic drugs (motor stimulation, sedation etc).

Since Giurgea's original criteria were first published, there has been little agreement as to what truly constitutes a nootropic compound. The most well defined criteria to date were established by Skondia in 1979. Skondia utilizes a metabolic approach, taking into account the pharmacological mode of action.








Skondia's Nootropic Criteria:

I. No direct vasoactivity
- A. No vasodilation
- B. No vasoconstriction

II. EEG activity: No change in basic rhythm
- A. Quantitative EEG: Increased power spectrum (beta 2 and alpha)
- B. Qualitative EEG: Decreased delta waves and cerebral suffering

III. Must pass blood-brain barrier
- A. Under normal conditions
- B. Under pathological conditions

IV. Must show metatolic activity in:
- A. Animal brain metabolism
- 1. Molecular
- 2. Physiopathological
- B. Human brain metabolism (clinical evaluation)
- 1. A-V differences
- a. Increased extraction quotients of O2
- b. Increased extraction quotients of glucose
- c. Reduced lactate pyruvate ratio
- 2. Regional cerebral metabolic rates (rCMR)
- a. Increased ICMR of O2
- b. Increased rCMR of glucose
- 3. Regional cerebral blood flow: Normalization

V. Minimal side effects

VI. Clinical trials must be conducted with several rating scales designed to objectify metabolic cerebral improvement.

--------------------------------------------------------------
Since nootropic criteria are still widely debated, only compounds classified as nootropic agents by the National Center for Biotechnology Information (NCBI) will be considered as such.

***WARNING***

NCBI does not follow the same stringent criteria laid out for nootropics above. Compounds may poses vasodilatory properties, toxicity etc.



-------------------------------



First synthesized in 1964, Piracetam is legal to import into the United Kingdom without a prescription and remains an uncontrolled substance in the United States. Piracetam is a derivative of the neurotransmitter GABA (Gamma Amino Butyric Acid). GABA is the primary inhibitory neurotransmitter, and is involved in the regulation of muscle tone.(1) While structurally related, piracetam does not interact with GABA receptors as indicated by low affinity. To date, piracetam's mechanism of action remains unclear.

Piracetam is chemically related to pyroglutamic acid (pyrrolidine Carboxylic Acid). Pyroglutamic acid is found in cerebrospinal fluid and is formed by post translational modification through the deamination of N-terminal glutamine to pyroglutamic acid. A two-month study was carried out in which 40 patients aged 65 and over, suffering from memory problems, received either pyroglutamic acid daily for two months, or a placebo. At the end of the study, the researchers found that the group taking pyroglutamic acid showed significant improvements in memory function, compared to the control group.(2) This may be due to the ability of pyroglutamic acid to improve blood circulation, which has been shown to enhance brain glucose utilization, thereby increasing mental energy.(3)

While an exact mechanism for the effects of piracetam remains unknown, it is likely that piracetam enhances brain metabolism by increasing blood flow, increasing the amount of circulating oxygen, thus enhancing glucose utilization (the primary fuel of the brain) just like pyroglutamic acid. Others have proposed that by interacting with the polar head groups of the phospholipid bilayer of cell membranes, piracetam is able to increase cell membrane fluidity.(4) This would help to support healthy neuron structure, and thus enhance communication efficiency. In reality, piracetam may do all of this and more by stimulating a cascade of events throughout the body. For instance, piracetam exhibits significant antioxidant-like properties due to inhibition of proinflammatory thromboxanes at higher doses (4.8-9.6g).(5) It even has been claimed that piracetam is as effective as aspirin in the secondary treatment of ischemic stroke; however, the sample size of the test group was small.(6)

Piracetam's ability to increase memory in healthy individuals has been noted at dosages of 1600mg, three times daily. Most individuals have very modest memory improvements while on piracetam, but studies have shown that in the case of traumatic brain injury, a greater response may be exhibited.(7) The ability of piracetam to prevent cognitive impairment after traumatic events also has been implicated in reducing the cognitive decline resulting from coronary bypass surgery. It seems piracetam is even able to remediate psychological trauma. Self-reports of improvements in anxiety and depression with associated cerebrovascular disorders have been noted in individuals taking piracetam.(8) This effect is even greater than that observed in memory improvement. One of the most remarkable findings to date is the ability of piracetam to combat the buildup of lipofuscin, a byproduct of the oxidation of fatty acids, in brain tissue associated with chronic alcohol consumption. It appears that piracetam is actually able to prevent the loss of neurons following alcohol binges while promoting greater plasticity.(9)

Piracetam use has been shown to result in a decrease in hippocampal acetylcholine levels, so it is typically co-administered with other cholinergic compounds. In animal models of aging, co-administration of piracetam with choline resulted in a synergystic increase in cognitive performance, with the greatest improvements in those with mild age-related cognitive decline.(10)

Effects can usually be felt within an hour or up to several days after consumption. Full efficacy may take up to a month. Typical dosage is between 800mg and 6 grams daily; with most individuals consuming between 1600mg-2400mg. Piracetam is typically taken in cycles, first daily for 2-3 months, followed by 1 month off. Piracetam may be co-administered with a choline source for enhanced results. While the upper tolerable daily intake of choline nears 3.5g (3500mg); low blood pressure, diarrhea, headache, and overstimulation may be experienced at much lower doses. Most users tend to find the greatest benefit from less than 500mg.

Adverse effects of piracetam are very rare, but may include insomnia, drowsiness and agitation. While most people experience improvements in anxiety, piracetam may worsen symptoms in some individuals. While it is true that piracetam's anxiolytic and antidepressant effects are in fact greater than its effects on memory, please use particular caution if you have anxious tenancies!

Human trials have shown piracetam consumption to be safe over the course of 18 months of investigation, at dosages of 3.2g per day. No significant adverse effects have been shown at doses as high as 20g per day, although the likelihood of headaches is known to increase with quantity consumed -- particularly when combined with choline. Piracetam is known to act synergistically with other compounds such as choline, aniracetam, oxiracetam, etc. Adjust dosage accordingly.

__________________________________________________

1. Watanabe M, Maemura K, Kanbara K, Tamayama T, Hayasaki H (2002). "GABA and GABA receptors in the central nervous system and other organs". Int. Rev. Cytol.. International Review of Cytology 213: 1–47. doi:10.1016/S0074-7696(02)13011-7. ISBN 978-0-12-364617-0. PMID 11837891.

2. Grioli S et al. Fundam Clin Pharmacol 1990;4(2):169-173

3. Lunshina EV et al. Eksp Klin Farmakol 2002;65(3):3-5

4. Moriau M, et al. Platelet anti-aggregant and rheological properties of piracetam. A pharmacodynamic study in normal subjects. Arzneimittelforschung. (1993)

5. Evers S, Grotemeyer KH. Piracetam and platelets--a review of laboratory and clinical data. Pharmacopsychiatry. (1999)

6. Dimond SJ, Brouwers EM. Increase in the power of human memory in normal man through the use of drugs. Psychopharmacology (Berl). (1976)

7. Batysheva TT, et al. Experience of the out-patient use of memotropil in the treatment of cognitive disorders in patients with chronic progressive cerebrovascular disorders. Neurosci Behav Physiol. (2009)

8. Brandão F, Paula-Barbosa MM, Cadete-Leite A. Piracetam impedes hippocampal neuronal loss during withdrawal after chronic alcohol intake. Alcohol. (1995) Brandão F, et al. Piracetam promotes mossy fiber synaptic reorganization in rats withdrawn from alcohol. Alcohol. (1996)

9. Mondadori C, Ducret T, Häusler A. Elevated corticosteroid levels block the memory-improving effects of nootropics and cholinomimetics. Psychopharmacology (Berl). (1992)

10. Pepeu G, et al. The relationship between the behavioral effects of cognition-enhancing drugs and brain acetylcholine. Nootropic drugs and brain acetylcholine. Pharmacopsychiatry. (1989)) Fontani G, Grazzi F, Meucci M. Effect of piracetam plus choline treatment on hippocampal rhythmic slow activity (RSA) and behavior in rabbits. Life Sci. (1984) Bartus RT, et al. Profound effects of combining choline and piracetam on memory enhancement and cholinergic function in aged rats. Neurobiol Aging. (1981).
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5hadow12ogue
post Jun 19, 2013, 07:38 PM
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Nice post and info Flex. I can't say how the moa's would effect each other completely for you, but you should be fine with taking piracetam.

I haven't had any issues with piracetam since I was first introduced to it, aside from headaches in the initial days.
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