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Amphetamine Neurotoxicity and Tolerance Reduction/Prevention

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Lithium and its effects on dopamine

Effects of lithium on dopamine D2 receptor expression in the rat brain striatum.
Kameda K, Miura J, Suzuki K, Kusumi I, Tanaka T, Koyama T.
Source
Department of Psychiatry, Hokkaido University School of Medicine, Sapporo, Japan. [email protected]
Abstract
Effects of lithium on the dopamine D2 receptor expression in the rat brain striatum were studied. Feeding the chow containing 0.2% LiCO3 for 6 days increased the level of the dopamine D2 receptor mRNA, and the transcription rate of the dopamine D2 receptor gene, indicating the stimulatory effects of lithium on the transcription of the dopamine D2 receptor gene. [3H] Spiperone binding to the striatal membranes increased in the rats treated with lithium, while the Western blotting analysis showed no change of the amount of the dopamine D2 receptors. These results suggested that lithium might induce the conformational changes of the dopamine D2 receptors. The methamphetamine-induced locomotor activity was enhanced by the pretreatment with lithium, whereas simultaneous increase in the methamphetamine concentration in the striatum was also observed. These observations suggested that the stimulation of methamphetamine-induced locomotor activity by lithium might be, at least partly, due to either increased sensitivity of the dopamine receptors, or increased concentration of methamphetamine in brain, or combination of both.
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Melatonin also appears to have a positive effect on VMAT2:
Neurosci Lett. 2011 Jan 20;488(2):154-7. Epub 2010 Nov 13.
Melatonin attenuates the amphetamine-induced decrease in vesicular monoamine transporter-2 expression in postnatal rat striatum.
Mukda S, Vimolratana O, Govitrapong P.
Source
Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakornpathom 73170, Thailand.
Abstract
The vesicular monoamine transporter-2 (VMAT-2) is responsible for packaging intraneuronal dopamine into synaptic vesicles in preparation for synaptic release and is a critical regulator of cytoplasmic dopamine levels and dopaminergic function. It has long been recognized that VMAT-2 is also a critical mediator of amphetamine-induced dopamine release. Amphetamine-induced lesions during development have the potential to produce numerous permanent abnormalities in neural circuitry and function. Therefore, in the present study, we investigated the effects of amphetamine on the levels of VMAT-2, α-synuclein and phosphorylated tyrosine hydroxylase in the striatum of neonatal rats. We found that chronic amphetamine administration in postnatal rats produces dopaminergic deficits in the striatum, including decreases in the levels of VMAT-2 and phosphorylated tyrosine hydroxylase. In addition, an increase in α-synuclein expression was observed in the striatum of postnatal rats following chronic amphetamine treatment. Furthermore, we identified a role of (10mg/kg) melatonin, a methoxyindole released from the pineal gland, in attenuating the detrimental effects of amphetamine on dopaminergic neurons.
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Epsilon Alpha said:
Maybe drinking just isn't for you then, but I do know the temptation in college especially in the states.

As far as the supplements go, try to be aware of possible interactions especially with adaptogens. But, if I had to give a daily essentials list for amphetamine users at below binge doses it would be this: curcumin, a multivitamin, CoQ10, magnesium, and melatonin.

Of course a responsible lifestyle plays a big role as well.
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Magnesium nearly doubles the half life of amphetamine apperantly by changing urine PH, i also agree with curcumin, melatonin, add to that holy basil.

Holy basil also might show promise in the treatment of amphetamine anxiety, altough this is mostly a gues based on its anxiolytic and calming effects, it appears to be a quite potent herb.
 
Im mistaken, the study's werent talking about magnesium specifically but about urine PH and amphetamine metabolism, during alkaline urine production, the half life of amphetamine changes dramatically, one way to change this is taking magnesium, id suspect a cumulative effect of combining antacids and magnesium, altough im not even sure wheter antacids have an effect on urine PH, they do change stomach absorbtion.

In all four subjects, amphetamine was cleared from the blood plasma at a much faster rate during the "acid-ash'' diet (when urinary pH was less than 6.0) than during the administration of sodium bicarbonate (urinary pH greater than 7.5). During production of acid urine, the half-life of amphetamine ranged from 8 to 10.5 hours, whereas during alkaline urine production the half-life of plasma amphetamine ranged from 16 to 31 hours.
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http://www.ncbi.nlm.nih.gov/pubmed/5285389
http://www.ncbi.nlm.nih.gov/pubmed/12324487
 
Hey, could you get the full text for the melatonin VMAT2 link?
If it shows some kind of activity at doses closer to 1mg/kg I think we have a winner, but 10mg/kg is a gram of melatonin for a 100kg man.
 
If anyone could get the full text for Medievil's melatonin study or this one I'd have some more info to work with.

http://onlinelibrary.wiley.com/doi/10.1046/j.1471-4159.1996.67020443.x/full

Brain-derived neurotrophic factor works coordinately with partner molecules to initiate tyrosine hydroxylase expression in striatal neurons
Xinyu Dua, Natalie D. Stulla and Lorraine Iacovitti

Abstract

Previous studies demonstrated that the cooperative interaction of acidic fibroblast growth factor (aFGF) and a partner molecule could induce the novel expression of the catecholamine (CA) biosynthetic enzyme, tyrosine hydroxylase (TH) in striatal neurons [Du and Iacovitti, J. Neurosci., in press; Du et al., J. Neurosci., 14 (1994) 7688–7694; Iacovitti et al., submitted]. The present study demonstrates that in addition to aFGF, brain-derived neurotrophic factor (BDNF) is also capable of moderate levels of TH induction (30% TH+ striatal neurons) when administered at high concentrations (100 ng/ml). As with aFGF, BDNF's activity dependent on its coupling to an appropriate partner molecule; the most potent of which were 10 μM dopamine (DA) and 50 μM mazindol. BDNF + DA-induced TH expression was first evident after at 12 h; peaked by 18 h and declined by 4 days in culture. Cyclohexamide eliminated nearly all and α-amanitin reduced by half the TH induction elicited by DA and BDNF; indicating that both de novo transcription and translation were required for increased expression. In contrast with aFGF and BDNF, other putative dopamine differentiation factors, such as glial-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF), were able to elicit barely detectable (10%) levels of TH induction, regardless of the partner molecule used. These studies suggest that aFGF and/or BDNF may work coordinately with partner molecules to initiate TH expression; while a number of factors including, CNTF and GDNF, may be involved in its subsequent modulation
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It looks like jlspartz was onto something with BDNF, it seems like it increases dopamine production which could explain its variable effects on cell metabolism and could have a positive effect on tyrosine hydroxylase. It could also keep your neurons a little bit further from apoptosis.

And for those of you who are curious, cucumin increases BDNF concentrations in the brain.
 
Epsilon Alpha said:
Hey, could you get the full text for the melatonin VMAT2 link?
If it shows some kind of activity at doses closer to 1mg/kg I think we have a winner, but 10mg/kg is a gram of melatonin for a 100kg man.
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what's the normal recommended dose of melatonin, .5-5 mg? I wonder what 200x the normal dose would do to a person?
 
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alienidentikit said:
what's the normal recommended dose of melatonin, .5-5 mg? I wonder what 200x the normal dose would do to a person?
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http://jcem.endojournals.org/content/45/4/768.abstract

Apparently not too much. Granted it would probably be really freaking expensive to dose a gram of melatonin a day.

I'd recommend melatonin dosages this high only in cases of MASSIVE binges. Melatonin at high doses does affect other hormone systems, but I'd say that 5mg a night in combination with other antioxidants should be a solid starting point for people on ADHD dosages of amphetamine.

J.Galt suggests PQQ for abuse level dosages, and upon checking the science I'd say he'd be right to do so.

I'm still going through the tyrosine hydroxylase paper, but I <3 you for posting these. Thanks man!
 
Fyasko. said:
MieDieViL & Epilson- thanks for all the work you're putting it, i (and probably a bunch of other users) appreciate it:)
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Also, sorry for missing your earlier question on curcumin. If start your amphetamine dosages on the low side its safe for everyday use, but it does accumulate (not a bad thing, but it can lead to MAOI like issues if you're quite careless).

IIRC Ex Dubio of Mind and Muscle takes 10mg d-amp a day and took curcumin for a long time and he noted significant potentiation.


In the truth we need anecdotal reports before we can say anything more than "well on paper it looks like solid gold". If you guys have noticed anything that affects how amphetamine affects you feel free to post it as long as you can give some dosage patterns :).

J.Galt was great for that, and turned me on to the lithium approach even before I read its effects on VMAT2.
 
Do you find it a little disturbing that the drug companies aren't doing this kind of research? It seems as though amphetamine neurotoxicity has been sort of swept under the rug, even though it's been known about since the 70s. There's a good chance that, with a little R&D, the drug companies could either find something to add to their product to make it safer, or a substitute drug could be found that is effective without toxicity. It shouldn't fall on amphetamine users and undergraduates to do the research.
 
Epsilon Alpha said:
J.Galt suggests PQQ for abuse level dosages, and upon checking the science I'd say he'd be right to do so.

I'm still going through the tyrosine hydroxylase paper, but I <3 you for posting these. Thanks man!
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Anybody try using PQQ?

Let me know if you need more journal articles, I can usually access most.
 
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alienidentikit said:
Anybody try using PQQ?

Let me know if you need more journal articles, I can usually access most.
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Will do man, thanks again :)

I'd actually like to see some more reports on PQQ if anyone is willing to trial it on themselves. J.Galt was on to something with this compound and only now am I starting to understand how it may affect both tolerance and toxicity.

NDMA channel modulator (presumably negative), has effects on both CREB and histones (which may affect tolerance but J.Galt never mentioned it), up-regulation of cell metabolism, RNS and ROS scavenger, prevents development of alpha-synuclein, and may have some effects on cell death pathways.

Also it looks like it mixes favorably with CoQ10.
Effect of pyrroloquinoline quinone (PQQ) on mental status of middle-aged and elderly persons". Food Style 21 13 (7): 50–52. 2009.
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If anyone's up for trying out various supplements like melationin, curcumin, PQQ, lithium, and CoQ10 so that we can have some user feedback I think that would be great! If you're interested just post it in this thread because I don't have PM yet.

It would let us work out what treatments subjectively help the most, and develop a better suited regime.

Hope its not against the rules to post places to by a non-recreational supplement, but if it is mods please remove the link.

http://www.lef.org/Vitamins-Supplements/Item01500/PQQ-Caps-with-BioPQQ.html
 
Not completely sure of the relevance of this study, but it shows that chronic lithium can increase tyrosine hydroxylase in rats. If it applies to humans it might help reduce the post amphetamine reduction in tyrosine hydroxylase seen in amphetamine addicts.

http://onlinelibrary.wiley.com/doi/10.1046/j.1471-4159.1998.70041768.x/pdf

Also, seeing as I lost the full text when I had to get a worm off my computer could someone post the lithium VMAT2 fulltext? I want to go a little more into its regional effects and how it might effect amphetamine users.
http://journals1.scholarsportal.info/details.xqy?uri=/00068993/v953i1-2/189_limteovirb.xml

Lithium may exert a protective effect against methamphetamine
http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=5829696

I'd also like to add the lecithin might help speed recovery from amphetamine induced damage by providing the raw materials to rebuild cell membranes. More of a personal theory on this one but my logic is solid.

Also, I'm human so if anyone notes mistakes in my posts feel free to point them out.

Edit: to the guy that mentioned NAC it may have some very interesting properties on addiction as well as being a antioxidant. We need more info on it. Also, could we get some info on ginseng if anyone wants to help out?
 
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ellekereljer said:
I promise to post my experience when the semester starts and I get back into routine again. Right now I am just preparing my body, mostly physically, with loads of exercise on my bike. Like I said I cut out adderall for a month and a half. Maybe a bit longer. I curtailed my caffeine to just green tea. From a couple cups of green tea down to one a day before my bike rides. Now zero caffiene. Much harder to work out/recover. Especially in the legs. Caffeine has some innate ability that works on the legs somehow. Its a good thing I never picked up the habit of exercising on addies because that would have been a bitch of a withdrawal symptom. Now, bopping in the club is a totally different thing.

I got memantine a week ago and looking at the empty pill sockets confirms it has been a week on memantine. I started 5mg morning/5 mg night. Heavy brain fog but yesterday that cleared up. My thinking is clear but in a different way. Hard to explain. It seems to be a good mood stabilizer. We shall see what this drug does longterm. Looks/feels promising. Dxm is just so grimey, I really do not want to resort to that shit.

Soon I will pop 2.5 mg adderall and see what it does. Ridiculous dose if you ask me but I am going to try to keep it low as possible. 5 mg twice a day is what I am shooting for but 10 mg twice a day would still be a good outcome. I am usually a 20mg x2 type of dude. I am not necessarily chasing that strung out feeling, I just want to feel good, clear thought, and less anxiety. It's Going to be real hard to cut a 20mg pill up in such n such way. Oh lord. Guestimatory no doubt. I can post my experience if you guys like but I think I am only going to get some real answers when therapeutical habituation takes place.

ps: curtailed is a nice word which I may or may not know the definition of. Also, guestimatory might not be a word. Just a little post script for you nice folks.
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Sounds like a solid plan :)
But, maybe using a liquid measure rather than cutting the pills up would be easier and more accurate.

Also, I'd like to say that if anyone's looking at the MAPK/ERK pathway and thinking "man that would be a great target to inhibit" you'd be right but I really wouldn't advise taking chemotherapy drugs if you don't have cancer.

Still a interesting paper to read:
http://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2004.02712.x/full
 
I don't mean to rain on anybody's parade, but how are you going to tell if this is working? I mean the neurotoxicity prevention part. This kind of brainstorming ideas is an important step toward an anti-tox cocktail, but it's only one step. Then you have to do experiments to prove that it actually works. And proving that it works in humans will be darn-near-impossible. Without the experiments, all you will be doing by taking these pills is making yourself feel better, and giving money to the supplements store. I'm not aware of any studies showing that losing those dopamine axons has any actual consequences, so I'm going to just assume you don't need them. Unless it's super-cheap and easy, I would feel too silly throwing money at supplements on the basis of a lot of conjecture and hoping to achieve a benefit that is entirely theoretical and can't be measured or detected.
 
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