Methamphetamine pharmacology and neurotoxicity

[jspun]

UingFSE aside which has produced a jumbled mess. Wondering about theories regarding mech of action regarding meth euphoria. Releases NE, 5-HT, DA but what is the basis for the magic this drug has that is lacking in phen/fen, wellbutrin/SSRI or similar combinations. What are current theories regarding mechanism of neurotoxicity, why does temp seem to increase extent. There was a paper published from the Univ of HI implying neurotoxicity continues for up to 6 months after last use in chronic users based on neuroimaging studies. Relibilty?

 

[nuke]

Methamphetamine releases large amounts of 5HT and dopamine/norepinephrine. The 5HT release elevates body temperature. The suspected metabolism of 5HT in dopaminergic neurons by MAO-B as well as the metabolism of DA/NE in these neurons by MAO-B releases hydrogen peroxide which forms reactive nitrogen and oxygen species. The nitrogen and oxygen species destroy mitochondrial DNA and induce cell death via caspase-3. They also cause toxic quinone metabolites of 5HT, DA and NE to be formed. The effect is vastly exacerbated by the increased body temperature.

My thoughts are that the neurotoxic effect of methamphetamine is permanent in nature for chronic users, mirroring the studies of cognitive assessment and imaging of the brains of users of the drug.

 

[jspun]

So how do you forstall this process in the framework of harm reduction? Could there be other substrates not yet identifyied that contribute to MA's MOA- any promising targets?

 

[nuke]

Use something with a lesser affinity for 5HT release (dextroamphetamine). Inhibiting MAO-B doesn't seem decrease neurotoxicity acutely after exposure to methamphetamine:

Biphasic effects of selegiline on striatal dopamine: Lack of effect on methamphetamine-induced dopamine depletion
Auteur(s) / Author(s)
GRASING Kenneth (1) ; AZEVEDO Romeu (2) ; KARUPPAN Steven (2) ; GHOSH Suchandra (2) ;

We tested the hypothesis that selegiline can attenuate dopamine depletion if administered following high doses of methamphetamine that cause neurotoxicity in the striatum. Methamphetamine produced decreases of 50% or greater in both striatal concentrations of dopamine and combined concentrations of homovanillic acid and DOPAC in mice. For animals not exposed to methamphetamine, chronic treatment with selegiline over 18 days caused biphasic effects on striatal dopamine content, with decreases, no effect, or increases observed for mice receiving treatment with 0.02, 0.2, and 2.0 mg/kg, respectively. Selegiline failed to modify methamphetamine-induced reductions in striatal dopamine content or combined concentrations of homovanillic acid and DOPAC. Significant increases in mortality following the onset of selegiline treatment (24 hours after the initial dose of methamphetamine) occurred in methamphetamine-treated mice that received saline or 2.0 mg/kg of selegiline, but not for mice treated with 0.02 or 0.2 mg/kg of selegiline. These results indicate that selegiline fails to attenuate dopamine depletion when administered chronically following exposure to methamphetamine, but may attenuate methamphetamine-induced mortality. In control animals that did not receive methamphetamine, low doses of selegiline produced decreases the concentration of striatal dopamine, while high dose treatment caused increases in striatal dopamine content.

Unfortunately I can't seem to get dextroamphetamine to substitute for methamphetamine for many addicts. They just love their methamphetamine, I guess. MAO-B inhibition before methamphetamine administration may be protective (I'm having trouble finding a reference for METH but it is for MDMA). Selegiline appears to be safe when co-administered with METH, but the sample size of the study is small, length short and not administered in humans.

Reduced cardiovascular effects of methamphetamine following treatment with selegiline

Charles W. Schindler, , a, Joanne P. Gilmana, Zofi Graczyka, Ganfeng Wangb and Winnie L. Geeb

a Preclinical Pharmacology Section, Behavioral Neuroscience Branch, DHHS/NIH/NIDA Intramural Research Program, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA

b Department of Biopharmaceutical Sciences, School of Pharmacy, University of California San Francisco, San Francisco, CA 94143, USA

Selegiline is a specific MAO-B inhibitor. As MAO-B has been shown to be significantly involved in the metabolism of dopamine in certain regions of the primate brain, selegiline has been proposed for use in the treatment of drug addiction. Selegiline is also metabolized in vivo to l-methamphetamine. Therefore, when given in combination with psychostimulants such as d-methamphetamine, there is the potential for adverse effects. To study this possibility, squirrel monkeys were treated with chronic selegiline and tested with two doses of d-methamphetamine (0.1 and 1.0 mg/kg, i.v.). Following at least 7 days of treatment with once daily 0.3 mg/kg i.m. selegiline, the effects of methamphetamine on blood pressure and heart rate were no different than the effects of methamphetamine observed prior to selegiline treatment. However, following at least 10 days of treatment with 1.0 mg/kg i.m. selegiline, the effects of methamphetamine on blood pressure and heart rate were significantly reduced. Both methamphetamine and amphetamine were detected in plasma following chronic selegiline treatment. When monkeys were given an acute selegiline injection prior to methamphetamine, reduced cardiovascular effects were also seen. These results indicate that selegiline can be used safely even in combination with methamphetamine, as the cardiovascular effects of the drug combination were no greater than either drug alone, and were actually reduced at the higher selegiline dose.

A trial in humans is ongoing: http://clinicaltrials.gov/ct2/show/NCT00033072

I don't know how safe the combination would be exactly, but it's not like METH is all too safe to begin with...

 

[jspun]

Unfortunately I can't seem to get dextroamphetamine to substitute for methamphetamine for many addicts.

Why does methamphetamine has greater acceptability among users compared to dexedrine. Greater lipophilicity?

 

[immad]

Meth releases quite a bit of serotonin compared to dex-amph. That, and it does possess a greater lipophilicity like you said.

 

[jspun]

Question is how would that make it more reinforcing. Seems like 5-HT release has an inhibitory effect on dopaminergic tone in certain parts of the brain related to reward.

 

[Recept]

I think it's just because the added serotonergic effects make the high feel better overall, and once you get used to it, something without that effect (eg dextroamphetamine) just doesn't cut it for you.

 

[Hammilton]

generally, those things with faster, stronger onset will be more rewarding. Meth > Amp, heroin > morphine etc etc

 

[theWorldWithin]

I suspect it has alot to do with the way 5-ht release makes the high subjectively 'smoother' with less jitters and PNS activity. Keep in mind the meth users generally ingest massive amounts of this compound at once. Even if you smoke only 100 mg of meth, think how much dextroamphetamine you would have to take to get equipotent effects then consider the PNS activity of such a dose.

Also I forgot to add, in high doses Dextro-amphetamine is also neurotoxic so if you tweak hard enough you are going to have to pay up one way or another.

Also the lifestyle of hardcore amphetamine users may predispose them to neurotoxicity because of lack of nutrients from not eating and sleep deprivation. So it is really a number of factors that contribure to the damage reguardless of the exact action on the neurochemical level.

 

[Hammilton]

Yeah, sleep dep has to be huge on these people. I'm an insomniac- you may notice that I post here at all hours of the day, there's a reason- and if I go 3-4 days without getting >3 hours of sleep a night, you can see the drain on me really quickly.

But then I will sleep for a week normally. For people who are routinely doing 72+ hours sleepless or with less sleep than I get, and repeating it as often as they can, I wonder how much of the long term physical changes can be attributed to the sleeplessness as to the drug itself.

 

[jspun]

Is the monamine release more a function of making the reuptake transporter work in reverse or r/t displacing (atleast catecholamines) from vesicles because of similarity in structure. Which has more of a profound effect? And why is SERT inhibited since amps are based on the catecholamine structure? Where is the binding site on SERT. Where is the binding site for cocaine on the transporters and does ritalin utilize the same site. Also what actually gets has a higher 5-HT/DA ratio in the synapse cocaine or methamphetamine? I know these are alot of questions but I felt like clumping. Last do neurohormones play a role in MA's MOA like (prolactin? or oxytocin? can't remember which one I heard theorized) and MDMA empathy? If you guys aren't too anoyed, please answer part or as much questions as possible. Hope these questions make sense.

Last before I forget, would amino supplements for their corresponding transmitters like tyrosine and tryptophan improve depletion ( assuming the person isn't malnurished which they most certainly are) or are the enzymes catalizing these RXNs saturated in the non malnurished state?