Epsilon Alpha
Bluelighter
Link to previous thread:
http://www.bluelight.ru/vb/threads/...rotoxicity-and-Tolerance-Reduction-Prevention
Now to sum up what we were talking about before:
Epigenetics:
There are various animal studies that suggest amphetamine produces a large portion of its sensitization via epigenetic changes primarily through CREB and histone deacetylase (HDAC) activity. However, if the mouse studies are to be applied to humans the picture becomes complicated. Co-administration of HDACI’s and amphetamine produces increased sensitization and conditioned place preference http://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2010.03321.x/full
Curcumin provides an interesting approach to this by inhibiting virtually every epigenetic mechanism under the sun, though the exact concentrations needed for significant inhibition of the various pathways in humans is still unknown at this point. CREB inhibition would stop the immediate-early response gene (IERG) activation and in turn long term epigenetic changes, while HDAC inhibition (a process downstream of CREB) would theoretically lead to an acute increase in sensitization and production of IERG proteins. Now during a “tolerance break” repeated HDACI application post amphetamine was shown to decrease sensitization which may be a relevant process in humans.
But, then there’s the possibility of histone acetyl transferase (HAT) playing a large role in the equation. Curcumin is a pretty bitching inhibitor of HAT, more so than HDAC in rats at least. This suggests that the potential negative effects of HDAC acutely on sensitization may not be an issue. http://www.ncbi.nlm.nih.gov/pubmed/20383415
But, going back to the IERG’s it appears that they also play a role in the NMDA antagonist mechanism of action via CREB http://www.jneurosci.org/content/16/13/4231.short. And, curcumin appears to have a effect on NMDA calcium influx too http://www.ncbi.nlm.nih.gov/pubmed/20015232.
So to sum it all up: curcumin is kind of like the sawn off shotgun of epigenetic modulators, showing promise on several fronts but with its 9/21 positive response rate we’d need better controlled anecdotal or actual clinical trials to make more sense out of it. Also, there may be glaring species differences with the various proteins curcumin binds between humans and rats/mice that I’m too lazy to check out (hint hint). Also, don’t be afraid of trialling more selective inhibitors of epigenetic mechanisms as long as you’re smart and methodical about it.
http://www.ncbi.nlm.nih.gov/pubmed/21466474
Sensitization vs Tolerance.
This is a particularly interesting issue, as it involves both epigenetics and the strengthening/weakening of a ton of pathways in the brain. I’ll fully admit that I’m not that well versed on the topic (somebody grab Ex Dubio
) but it plays into the idea that a portion of "tolerance" may be specific pathways in the brain adapting to amphetamine use.
To discuss: TAAR, MGluR, NAChR, 5HT3R, long term potentiation, and further mechanism of cell death/dysfunction.
http://www.bluelight.ru/vb/threads/...rotoxicity-and-Tolerance-Reduction-Prevention
The Basic Stack.
- ~250mg elemental magnesium at bed. Why: magnesium deficiency is extremely common and known to worsen neurotoxic measures in mouse models. May also help with bruxism (jaw clenching)
- ~1-5mg sublingual melatonin 3 hours before bed. Why: helps regulate sleep cycle, potent antioxidant, several neuroprotective mechanisms.
- Stay hydrated, preferably with high quality fruit juices (such as 100% blueberry) Why: do I really need to explain this?
- Eat a balanced diet rich in dark fruits and vegetables. Why: Why: do I really need to explain this? Make sure you eat period.
- Avoid overheating. Why: Elevated body temperature has been linked to increased neurotoxicity in mouse models
- Coenzyme Q10 at 100mg/day in a softgel or oil based formulation (preferably taken with food). Why: extremely long half life antioxidant, various beneficial effects on mitochondrial function.
- Avoid sleep deprivation. Why: your body needs sleep whether you want to or not.
- A good multivitamin, or at the very least vitamins A,C,E, and D as well as selenium at a significant portion of the RDA value. Malnutrition is a very real concern with amphetamine use,
-Low dose ASA ~81mg/day, anti-inflammatory drugs have shown to reduce neurotoxic measures in several models, also might give your cardiovascular system a break.
- Keep your dose as low as possible.
Now to sum up what we were talking about before:
Epigenetics:
There are various animal studies that suggest amphetamine produces a large portion of its sensitization via epigenetic changes primarily through CREB and histone deacetylase (HDAC) activity. However, if the mouse studies are to be applied to humans the picture becomes complicated. Co-administration of HDACI’s and amphetamine produces increased sensitization and conditioned place preference http://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2010.03321.x/full
Curcumin provides an interesting approach to this by inhibiting virtually every epigenetic mechanism under the sun, though the exact concentrations needed for significant inhibition of the various pathways in humans is still unknown at this point. CREB inhibition would stop the immediate-early response gene (IERG) activation and in turn long term epigenetic changes, while HDAC inhibition (a process downstream of CREB) would theoretically lead to an acute increase in sensitization and production of IERG proteins. Now during a “tolerance break” repeated HDACI application post amphetamine was shown to decrease sensitization which may be a relevant process in humans.
But, then there’s the possibility of histone acetyl transferase (HAT) playing a large role in the equation. Curcumin is a pretty bitching inhibitor of HAT, more so than HDAC in rats at least. This suggests that the potential negative effects of HDAC acutely on sensitization may not be an issue. http://www.ncbi.nlm.nih.gov/pubmed/20383415
But, going back to the IERG’s it appears that they also play a role in the NMDA antagonist mechanism of action via CREB http://www.jneurosci.org/content/16/13/4231.short. And, curcumin appears to have a effect on NMDA calcium influx too http://www.ncbi.nlm.nih.gov/pubmed/20015232.
So to sum it all up: curcumin is kind of like the sawn off shotgun of epigenetic modulators, showing promise on several fronts but with its 9/21 positive response rate we’d need better controlled anecdotal or actual clinical trials to make more sense out of it. Also, there may be glaring species differences with the various proteins curcumin binds between humans and rats/mice that I’m too lazy to check out (hint hint). Also, don’t be afraid of trialling more selective inhibitors of epigenetic mechanisms as long as you’re smart and methodical about it.
http://www.ncbi.nlm.nih.gov/pubmed/21466474
Sensitization vs Tolerance.
This is a particularly interesting issue, as it involves both epigenetics and the strengthening/weakening of a ton of pathways in the brain. I’ll fully admit that I’m not that well versed on the topic (somebody grab Ex Dubio

A very interesting study came out a couple weeks ago, and though it's hard to say how relevant the implications are to humans, the study nonetheless puts forth some very intriguing ideas.
First, a quick refresher. Sensitization is a rather complex process that occurs when rodents are given [strongly] DAergic drugs or, as they are commonly known, "drugs of abuse". Sensitization refers to the phenomenon in which responding to a drug (measured typically by means of locomotor activity) is increased with repeated administration. For example, locomotor responding to amphetamine tends to increase -- not decrease, as would be expected with tolerance -- when amphetamine is given repeatedly, assuming a few technical criteria are met. What is particularly important, though, is that sensitization persists after months -- and even years -- of abstinence from a given drug.
Now, the catch is that we don't really even know if sensitization occurs in humans, but sensitization is nonetheless often taken as a model for the maladaptive neurological changes that occur in addiction. (Note that it may be that sensitization and tolerance happen simultaneously, but are expressed differently, in humans. It's not clear to me how well we can judge tolerance (i.e. to rewarding effects) in rodents.) So, assuming that sensitization -- or something like it -- occurs in humans, being able to quickly "break" sensitization -- which seems to otherwise persist indefinitely -- could completely change the landscape of addiction treatment. If fact, if the link between sensitization and addiction is correct, then "breaking" sensitization could be a rapid "cure" for addiction. Note that it is quite possible that this is precisely what compounds like ibogaine do.
As if that weren't enough, I have a pet theory that sensitization may be related to the development of motor complications like bruxism with extended use of amphetamine, cocaine, MDMA, and similar drugs. As many an MDMA user can attest, being able to prevent the bruxism that often accompanies frequent MDMA use would be a major boon.
And "breaking" sensitization is precisely what these researchers claim they have accomplished, with a rather unorthodox combination of a D1/D2 agonist (pergolide) and either a 5-HT3 antagonist (ondansetron) or a 5-HT2A/2C antagonist (ketanserin). Though the protocol might be tricky to adapt to humans, and suitable drugs might be hard to obtain, if it can truly reverse what we believe to be the manifestations of sensitization in humans, it would be game-changing. So without further ado, I present the study:
Behav Brain Res. 2011 Sep 30;223(1):227-32. Epub 2011 May 7.
Reversal of long-term methamphetamine sensitization by combination of pergolide with ondansetron or ketanserin, but not mirtazapine.
Bhatia KS, Szabo ST, Fowler JC, Wetsel WC, Lee TH.
Source
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
Abstract
Psychostimulant abuse represents a psychiatric disorder and societal concern that has been largely unamenable to therapeutic interventions. We have previously demonstrated that the 5-HT₃ antagonist ondansetron or non-selective 5-HT(₂A/₂C) antagonist ketanserin administered 3.5 h following daily pergolide, a non-selective DA agonist, reverses previously established cocaine sensitization. The present study was conducted to evaluate whether the same treatments or delayed pairing of pergolide with the antidepressant mirtazapine can also reverse consolidated methamphetamine (METH) behavioral sensitization. Sprague-Dawley rats received METH infusion via osmotic minipumps (25 mg/kg/day, s.c.) for 7 days, with accompanying daily injections of escalating METH doses (0-6 mg/kg, s.c.). This regimen takes into account the faster elimination of METH in rats, and is designed to replicate plasma METH concentrations with superimposed peak drug levels as observed during METH binging episodes in humans. Following a 7-day METH withdrawal, ondansetron (0.2 mg/kg, s.c.), ketanserin (1.0 mg/kg, s.c.), or mirtazapine (10mg/kg, i.p.) was administered 3.5 h after pergolide injections (0.1 mg/kg, s.c., qd) for 7 days. Behavioral sensitization as a model of METH abuse was assessed 14 days after the combination treatment cessation (i.e., day 28 of METH withdrawal) through an acute challenge with METH (0.5 mg/kg, i.p.). Pergolide combined with ondansetron or ketanserin reversed METH behavioral sensitization, but pergolide-mirtazapine combination was ineffective. The role of reactivation of addiction "circuit" by a non-selective DA agonist, and subsequent reconsolidation blockade through 5-HT₃ or 5-HT₂ antagonism in reversal of METH sensitization and treatment of METH addiction is discussed.
Copyright © 2011 Elsevier B.V. All rights reserved.
PMID:21571009 [PubMed - indexed for MEDLINE]
PMCID: PMC3113440 [Available on 2012/9/30]
http://www.mindandmuscle.net/forum/neuroscience-nootropics/40750-sensitization-breakthrough-2.html
To discuss: TAAR, MGluR, NAChR, 5HT3R, long term potentiation, and further mechanism of cell death/dysfunction.
Last edited: