33 replies to this topic

[chrono]

I wanted to bump this topic, and re-emphasize one of the most interesting papers I've found about memantine. Dilenja mentioned it in post #26, but here it is again:

In vitro galantamine-memantine co-application: mechanism of beneficial action.
Zhao X, Marszalec W, Toth PT, Huang J, Yeh JZ, Narahashi T.

Several drugs are in clinical use for symptomatic treatment of Alzheimer's disease patients. Since Alzheimer's disease is known to be associated with down-regulation of the cholinergic and N-methyl-D-aspartate (NMDA) systems, most of these drugs inhibit acetylcholinesterase, potentiate the activity of nicotinic acetylcholine receptors (nAChRs), or modulate NMDA receptors. Galantamine is an anticholinesterase and allosterically potentiates the activity of the nicotinic receptors. We have recently found that galantamine potentiates the activity of NMDA receptors as well. Memantine is unique in that it inhibits the NMDA receptors. We have developed a hypothesis that combining galantamine and memantine will be more effective for improving the patient's conditions than monotherapy with either drug. Patch clamp and intracellular Ca(2+) imaging experiments using rat cortical and hippocampal neurons clearly provided the in vitro bases for our hypothesis. Memantine blocked the extrasynaptic NMDA receptor 100 times more potently than the synaptic NMDA receptor at negative membrane potentials and the block of both types of NMDA receptors was attenuated with depolarization. However, galantamine potentiation of the NMDA receptors was not voltage dependent. Thus, co-application of memantine with galantamine prevented the galantamine potentiation and the activation of extrasynaptic NMDA receptors, but membrane depolarization revealed the galantamine potentiation. Therefore, cell death is expected to be prevented by memantine near the resting potential while the NMDA-mediated synaptic transmission, which is down-regulated in the patients, is maintained and potentiated by galantamine. These results provide in vitro bases for the beneficial actions of galantamine and memantine combinations.

PMID: 17011596 [PubMed - indexed for MEDLINE]

This sounds like a very elegant combination of mechanisms. While their focus was on AD and neuroprotection, the normalization of NMDA function as well as nAChR a7 might attenuate some of the cognitive deficits reported with memantine. However, I guess interference with the NMDA antagonism might prevent the tolerance-preventing effect we're looking for in the first place. From the abstract, it's not really clear whether synaptic NMDA would be potentiated or blocked when the neuron is at rest (negative potential).

@aLurker: I read your brief mention of trying this over on M&M. Could you give us some more detail about your memantine experience, and what (if any) effect galantamine had?

Edited by chrono, 18 November 2010 - 07:19 PM.
clarity (insomnia)

[aLurker]

Well I only used it for 10 days and those 10 days were horrible. I've never felt so retarded in my entire life, I couldn't take it anymore so I quit. It was like being a drunken idiot trying to deal with your daily life. Granted, perhaps it gets better after the adaptation period and I went straight for the full 20 mg/day. There are at least two studies showing lingering negative effects though so I'm staying away from memantine. I talked a little bit more about my experience and concerns in this thread.

To sum up my experience:
No wonder they say the drug is well tolerated in Alzheimer's trials since it has side effects indistinguishable from dementia itself. I'm just glad I didn't become retarded enough to continue taking it. It might help some people but personally I don't consider it worth the risk of slight impairments since I'm not really the compromising type when it comes to my intellect.

[aLurker]

I desperately tried to alleviate the side effects during the adaptation period but nothing seemed to work entirely. I tried aniracetam, piracetam, oxiracetam, nicotine, galantamine, ALCAR... you name it. Nothing took away the stupidity. Perhaps some of the stuff helped a little but not enough to make me normal. Some people say they adapt to it very quickly though, in a matter of a couple of days. I might just be one of the unlucky ones who can't tolerate it all that well.

[Reformed-Redan]

I desperately tried to alleviate the side effects during the adaptation period but nothing seemed to work entirely. I tried aniracetam, piracetam, oxiracetam, nicotine, galantamine, ALCAR... you name it. Nothing took away the stupidity. Perhaps some of the stuff helped a little but not enough to make me normal. Some people say they adapt to it very quickly though, in a matter of a couple of days. I might just be one of the unlucky ones who can't tolerate it all that well.

I've been reading through experience reports with memantine. It seems that people as they usually are, are very impatient, especially those with ADD, and want immediate results. No wonder they can't get through the initial renormalization phase of memantine. I think, over time you should be able to up-regulate enough alpha-7-nicotininc receptors to augment the brain fog associated with memantine. I am still worried about the dissassociative effects with memantine.

Sort of a humdrum with this one.

Most of the people who actually were happy with memantine scheduled their dosing regiments to 5mg at 6 and 5 mg at 4 and just keept on going on with that. After about 6 months they say the brain fog went away and the desired effects, tolerance reduction remained. I'm going to have a busy schedule now; so, I don't have the time to go through 6 months of potential brain fog.

Ehh