Posted by undopaminergic on June 1, 2008, at 17:49:36
In reply to Re: Parnate and Suboxone? » undopaminergic, posted by SLS on May 30, 2008, at 4:59:07
> Thanks a bunch for the information. I would not have known which opioids were safe to use in combination with Nardil.
>By the way, the full article on MAOIs and opioids by Dr. Gillman is freely available:
http://bja.oxfordjournals.org/cgi/content/full/95/4/434
http://bja.oxfordjournals.org/cgi/reprint/95/4/434.pdf> As far as using stimulants, that would make sense to try first. Unfortunately, as a former substance abuser, his doctor will probably keep clear of them.
>The abuse risk can be substantially minimised by using stimulants that are difficult (ie. not worth the effort) to use in a non-intended manner, such as Concerta or Vyvanse, and further by prescribing limited amounts at a time.
> Out of curiosity, how does the synergism work among the four drugs: stimulants, Nardil, memantine, and suboxone?
>As a partial mu-agonist buprenorphine (BUP) quenches GABA output in the vental tegmental area (VTA), resulting in disinhibition and increased firing of VTA dopamine (DA) neurons, causing enhanced DA release in the nucleus accumbens (NAc). BUP also blocks kappa-opioid receptors (KORs), some of which are located on DA nerve terminals (in the NAc an elsewhere) and inhibit DA release when stimulated by endogenous dynorphin or exogenous kappa-agonists. Because stimulants seem to increase dynorphin release in the NAc, the blockade of KORs by BUP contributes to preventling a dynorphin-mediated attenuation of DA release in the NAc. Furthermore, stimulation of KORs produces deleterious changes in the longer term, including a reduction in DA D2-receptor density (pre- and postsynaptic) and a downregulation of the dopamine transporter protein, of which both mechanisms diminish responsiveness to stimulants. Moreover, activation of somatodentritic KORs located on a subset of VTA DA neurons projecting to the prefrontal cortex (PFC), inhibits the firing of these neurons and results in a decline of DA levels in the target region (PFC) - this can be expected to impact working memory, executive function, and some other higher cognitive functions.
Memantine, probably via its blockade of NMDA-receptors (I haven't studied the precise details), prevents, attenuates or reverses tolerance to opioids, such as BUP, and thus helps maintain efficacy of the drug. Because memantine also shows considerable promise in diminishing the development of tolerance to stimulants, the opportunity for synergism is further increased. Since memantine has antidepressant and stimulant-like qualities of its own, it may provide benefits beyond the prevention of tolerance to other drugs.
I currently don't have any data on how Nardil might interact with memantine or BUP. However the increased synaptic concentrations of DA resulting from BUP and/or stimulants would be further enhanced by the MAO inhibition of Nardil, although the increase would be attenuated by stimulation of presynaptic autoreceptors. There is also the complication of diminished synthesis of neurotransmitters in response to MAO inhibition, and I would not expect a significant effect on this from the other drugs, although the possibility can't be ruled out. One possiblity is that the combined use of the other drugs might rended low doses of Nardil effective, allowing maintenance of a degree of MAO inhibition low enough not to trigger the downregulation of neurotransmitter synthesis. This is mostly unexplored - or at least undocumented - territory.
poster:undopaminergic
thread:831481
URL: http://www.dr-bob.org/babble/20080528/msgs/832391.html