Theory re: Ketamine & preventing amphetamine tolerance - please help explain

[AlexxRed]

Hi all,

Firstly I want to say that I would really appreciate some further information regarding this topic. And that I am NOT looking to attempt some reckless personal experiment.

I have been told that interspersed usage of ketamine (whilst abstaining from amphetamine) can prevent (or even reverse?) amphetamine tolerance. If this is theoretically possible what sort of dosages/regime would be required to obtain results?

And lastly is ketamine theoretically effective because it is a full NMDA antagonist or is there more at play when it comes to Ketamine that means it can be used to prevent (or reverse?) amphetamine tolerance?

Cheers

Alex

 

[BilZ0r]

I've been looking into this, I was sure there was some published, experimental data to support this idea, but I can't find it any more. Is there any reason to suspect this, there's lots of stuff looking at NMDA, methamphetamine and sensitization, but that is (probably) the complete opposite effect.

 

[AlexxRed]

^^^^^^

when I PM'd fastandbulbus re: reversing amphetamine tolerance he mentioned that the only method that he was aware of was interspersed ketamine use.

Are you saying that instead of preventing or reversing tolerance that what might actually occur is hyper sensitization?

 

[5-HT2]

I've been looking into this, I was sure there was some published, experimental data to support this idea, but I can't find it any more.

Me too. Oh well, I guess we'll keep on looking.

 

[vecktor]

not ketamine exactly but MK801, noncompetitive NMDA antagonists (channel blockers) seem to prevent sensitisation, (reverse tolerance) I suppose because NMDA channel blockers reduce neuronal plasticity(if that is the right term), normal tolerance has to do with receptor down regulation depletion of monoamines, and other non nmda mediated effects as far as I can tell. I'm also pretty sure that if it reduced normal tolerance the studies reporting on NMDA antagonists and reverse tolerance would have found it.

Blockade of 'reverse tolerance' to cocaine and amphetamine by MK-801

Karler, R., Calder, L.D., Chaudhry, I.A., Turkanis, S.A. 1989 Life Sciences 45 (7), pp. 599-606 244

'Reverse tolerance' was produced in rats and mice by repated exposure to either cocaine or amphetamine. The locomotor-stimulant effect was studied in mice; stereotypy and convulsions in rats. MK-801, the NMDA antagonist, blocked the development of 'reverse tolerance' to all three effects. In contrast, haloperidol selectively blocked 'reverse tolerance' to cocaine-induced sterotypy but not to convulsions. The data suggest that the glutamate system participates in the mechanism of 'reverse tolerance' to the dopaminergic effects of cocaine and amphetamine, as well as to the convulsant effect of cocaine.

the role of excitatory amino acids in behavioral sensitization to psychomotor stimulants

Wolf, M.E. 1998 Progress in Neurobiology 54 (6), pp. 679-720 457

Behavioral sensitization refers to the progressive augmentation of behavioral responses to psychomotor stimulants that develops during their repeated administration and persists even after long periods of withdrawal. It provides an animal model for the intensification of drug craving believed to underlie addiction in humans. Mechanistic similarities between sensitization and other forms of neuronal plasticity were first suggested on the basis of the ability of N-methyl-D-aspartate (NMDA) receptor antagonists to prevent the development of sensitization [Karler, R., Calder, L. D., Chaudhry, I. A. and Turkanis, S.A. (1989) Blockade of 'reverse tolerance' to cocaine and amphetamine by MK-801, Life Sci., 45, 599 606]. This article will review the large number of subsequent studies addressing: (1) the roles of NMDA, ?-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and metabotropic glutamate receptors in the development and expression of behavioral sensitization, (2) excitatory amino acids (EAAs) and the role of conditioning in sensitization, (3) controversies regarding EAA involvement in behavioral sensitization based on studies with MK-801, (4) the effects of acute and repeated stimulant administration on EAA neurochemistry and EAA receptor expression, and (5) the neuroanatomy of EAA involvement in sensitization. To summarize, NMDA, AMPA metabotropic glutamate receptors all participate in the development of sensitization, while maintenance of the sensitized state involves alterations in neurochemical measures of EAA transmission as well as in the expression and sensitivity of AMPA and NMDA receptors. While behavioral sensitization likely involves complex neuronal circuits, with EAAs participating at several points within this circuitry. EAA projections originating in prefrontal cortex may play a particularly important role in the development of sensitization, perhaps via their regulatory effects on midbrain dopamine neurons. The review concludes by critically evaluating various hypotheses to account for EAA involvement in the development of behavioral sensitization, and considering the question of whether EAA receptors are involved in mediating the rewarding effects of psychomotor stimulants and sensitization of such rewarding effects.

Alteration of neuronal activities following repeated administration of stimulants

Amano, T., Matsubayashi, H., Sasa, M. 2002 Nihon Arukoru Yakubutsu Igakkai zasshi = Japanese journal of alcohol studies & drug dependence 37 (1), pp. 31-40 4

It has been well-known that abuse of psychostimulants such as amphetamine and methamphetamine (MAP) induces behavioral sensitization (reverse tolerance) to MAP, resulting in psychotic effects such as hallucinatory-delusional state. Animals treated with MAP repeatedly also show the behavioral sensitization to MAP. This paper focuses on the pathogenesis and mechanism underlying sensitization to MAP after repeated treatment with MAP. MAP is known to release dopamine (DA), noradrenalin (NA) and serotonin (5-HT), and bind with the same sites on DA-, NA- and 5-HT-transporters as do these monoamines, thereby inhibiting re-uptake of these substances. As a result, these monoamines accumulate in the synaptic areas unnerved by the monoamine systems. An increase in the monoamines also occurs in the dendritic areas of DA, NA and 5-HT cells probably by a mechanism similar to those in the presynaptic terminals of monoamines. Releases and syntheses of DA, NA and 5-HT are inhibited by the monoamine per se via their autoreceptors such as D2, alpha 2 and 5-HT1A receptors, respectively. It is noteworthy that repeated MAP treatment results in the reduction of DA transporters, and such a decrease in transporters has been also found in MAP abusers by PET studies, suggesting a decrease in DA transporters is related with the appearance of reverse tolerance. Repeated MAP administration induces immediate early gene such as c-fos, c-jun and arc, and the increase in arc is inhibited by D1 and NMDA antagonists, suggesting an important role of such genes in inducing reverse tolerance. In electrophysiological studies using anesthetized rats treated with MAP repeatedly, hyposensitivities and hypersensitivities to DA and MAP have been found in nucleus accumbens receiving dopaminergic input from ventral tegmental area, 24-30 h and 5 days after the final administration of MAP, respectively, although the sensitivities recovered to the normal level 10 days after the treatment. The hypersensitivities were probably mediated via D1/D2 receptors. Thus, the hypersensitivities of nucleus accumbens neurons to DA and MAP are actually completed after repeated treatment of MAP. Therefore, it is of great interest to elucidate the molecular mechanism responsible for the DA receptor hypersensitivity.

 

[MeDieViL]

anecdotally there are a few reports of DXM preventing amphetamine (adderall) tolerance
i dont know how it works tough

 

[LuxEtVeritas]

10-30mg/day memantine should suffice to counter tolerance
Taken some supplemental Mg may also be of benefit here

Ketamine would not be the best choice for this purpose, but the above two agents should work

 

[Jabberwocky]

Ketamine is also pretty addictive in its own right. So, if you are looking to counteract tolerance with ketamine (which may be an indication that you are abusing stimulants) you may want to watch out for a creeping K addiction.

Just some h reduction from the peanut gallery...now back to pharmacology...

 

[BilZ0r]

yeah, they're lots of stuff on sensitization, but sensitization is the complete opposite of tolerance.

 

[vecktor]

yeah, they're lots of stuff on sensitization, but sensitization is the complete opposite of tolerance.

well for what its worth and I don't know much about it but I don't believe ketamine or any other NMDA channel blocker has any effect on traditional tolerance of amphetamines.

A large number of papers on preventing sensitisation (reverse tolerance) and not one mentions reversal of normal tolerance and if this effect was there one would have thought they would have found it.
perhaps the confusion is using terms like 'reverse tolerance' and people see it as 'reversing tolerance'.

Bilzor: how is traditional amphetamine tolerance mediated? receptor down regulation, depletion of catecholamine reserves, or lots of mechanisms?

I did run into some interesting stuff about 5HT6 antagonism to enhance amphetamine and this might be a more fruitfull avenue.

 

[Whitespy420]

I have a theory, and blast me all you want for it not being scientifically sound, but its more based on sensitization vs tolerance.

I've found NMDA chnnel blockers (my limited experience to small amounts of ketamine and DXM) and to a lesser extent magnesium coadministered with amphetamine (at least dextroamphetamine, I haven't replicated with methyl) lowers the "pleasure rush" and provides for a background feeling of stimulation rather than a direct push against your concious nervous system.

That being said, after 7 or 8 administrations with said NMDA blocker, euphoria returned but not at a lower level of amphetamine dosage.

Just my .02.