sam-E interacting with GABA drugs?

[TouchN' Stuff Blvd]

Hello. I understand that I may not really be ADD material, however I was wondering if someone here could help me understand this article.

I have been taking sam-e and would like to know what this suggests about possible interactions diazepam.

Abstract
The effect of phospholipid methylation on both [3H]diazepam and [3H]GABA ( [3H]gamma-aminobutyric acid) binding to crude synaptic plasma membrane from rat cerebellum has been studied. S-Adenosylmethionine (SAM) stimulates [3H]methyl group incorporation into membrane phospholipids and enhances [3H]diazepam binding by increasing the apparent Bmax. Conversely, inhibition of [3H]methyl group transfer from [3H]SAM to phospholipids by preincubation with SAM at 0 degrees C or with SAH abolishes the increase of binding. After preincubation with SAM, analysis of the GABA binding reveals the presence of binding sites with high affinity, a property absent in control membranes preincubated without SAM. Among the neurotransmitter bindings tested, only those of GABA and benzodiazepine in the cerebellum and beta-adrenergic ligands in the cerebral cortex are enhanced upon stimulation of phospholipid methyltransferase activity. [3H]Dihydromorphine, [3H]dihydro-alpha-ergokryptine and [3H]spiroperidol bindings are not affected by SAM. The present data suggest an involvement of phospholipid methylation in regulation of both [3H]GABA and [3H]-diazepam binding.

The article can be found http://www.ncbi.nlm.nih.gov/pubmed/6308156
sort of

 

[Solipsis]

Benzo's like diazepam bind to GABA receptors. Those receptors are proteins imbedded in the synaptic membrane of neurons. The membrane itself is a layer composed of phospholipids, a kind of fat.

What this research suggests is that SAMe (a methylating antioxidant) changes the makeup of compounds in the membrane, namely changes to those fatty compounds. Changing this composition can have consequences for structures or organelles IN the membrane such as the receptors I mentioned. Apparently the Bmax is increased meaning the density of receptors. I think that is because neuronal membranes treated with SAMe 'stack' together differently allowing more GABA receptors to be present. It seems this only works for GABA receptors. They compared it to check this.

An increase in GABA receptor density is said to enhance diazepam binding, obviously because it has more places to bind and consequently more effect to exert.

There is nothing quantitative anywhere in the abstract, I have no further access, but even with experiment data this would be very hard to translate to any measure of potentiation of any and all GABAergic effects including those from benzodiazepines.

I am not sure if you wanted layman terms but there is very little to say about what this should mean in practice, from what I can tell - so I tried to explain the theory.

Me, I'm the dropout here so you might want to wait on the professionals.

 

[sekio]

SAMe is a charged species and hence orally administered SAMe will likely not make it past the blood brain barrier.

That paper demonstrates the effects of SAMe on rat brain homogenate, not on live rats. From my POV the practical implication is that SAMe will do nothing in healthy individuals.

 

[Solipsis]

Charged? Can it not be administered in zwitterionic form like psilocybin? Or is that different because psilocybin can undergo ester hydrolysis?

Google it, there is suggesting evidence that SAMe can cross the BBB intact. Although I have yet to verify that data.

Methods

Rats were given SAMe and methionine orally [to rats] at various doses, and biochemical and behavioural testing was carried out at intervals up to 6 hours later.

Results

Methionine raised SAMe levels in various regions of the CNS and increased tail-flick latency, both at lower doses than SAMe

.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC543840/

Low levels of SAMe have been reported in the cerebrospinal fluid (CSF) of severely depressed patients. Oral and parenteral administration of SAMe result in a rise in CSF SAMe concentrations, indicating the compound crosses the blood-brain barrier.

http://ajp.psychiatryonline.org/article.aspx?articleid=102409

And last but not least:

S-adenosylmethionine is substrate for carrier mediated transport at the blood-brain barrier in vitro.

http://www.ncbi.nlm.nih.gov/pubmed/12031851

 

[sekio]

AFAIK, zwitterions are not easily transported either, and it is ester hydrolysis to psilocin that imbues psilocybin with activity. Amino acids, for instance, are charged enough as neutral forms to have their own transporters to move them through the gut and brain.

Unless there exists a mechanism for transporting SAMe around in the brain (think ATP / sodium transport) I would put money on it being demethylated to a noncharged form before beign transported, & remethylated on the other side of the BBB.

Of course SAMe is also capable of methylating other compounds too, so there's nothing stopping SAMe from exerting its effects by increasing, say, levels of choline...

 

[Solipsis]

Please check my previous post again about (among other things) SAMe being a substrate for the nucleoside carrier system.

Anyway I have great doubts as well that SAMe would have significant interaction with benzodiazepine effect, if there would actually be significant GABA receptor population changes wouldn't you see sedative effects from SAMe alone? Or would autoreceptors compensate for that?

 

[sekio]

[SAMe administration] enhances [3H]diazepam binding by increasing the apparent Bmax [of diazepam]

I interpret this as to mean that SAMe will increase the binding of diazepam to the BZD site and hence increase the potency of diazepam, if administered in significant enough quantities. This does not neccesarily mean that SAMe increases GABA binding on its own, or as you said it would be a GABAergic sedative. I expect it would not be hard to verify the potentiating effects (or lack thereof) of SAMe on diazepam.

Also, Wikipedia notes that SAMe may cause serotonin syndrome? Strange.

Please check my previous post again about (among other things) SAMe being a substrate for the nucleoside carrier system.

Unsuprising. I half-expected that that was the case. My assumption that SAMe does not cross BBB is obviously unfounded. I still maintain that many charged/highly polar species do not make it across BBB without an active transporter.

 

[Solipsis]

I interpret this as to mean that SAMe will increase the binding of diazepam to the BZD site and hence increase the potency of diazepam, if administered in significant enough quantities. This does not neccesarily mean that SAMe increases GABA binding on its own, or as you said it would be a GABAergic sedative. I expect it would not be hard to verify the potentiating effects (or lack thereof) of SAMe on diazepam.

Ohh well no, I didn't mean it to be a GABA ligand, but rather that if GABA receptors are 'upregulated' (probably not a correct word here), endogenous GABA would be potentiated would it not? Hence my question about autoregulation via for example auto-receptors, since for some reason I would expect there to be some part of the 'circuit' to prevent something like that.
In other words: I don't see why diazepam should have more effect but not endogenous GABA, unless GABA production would be adjusted. Which would suck if receptor density returns to normal. Instant withdrawal in theory. But I feel like this is not how it works. I keep wondering how it does work though.

 

[sekio]

After preincubation with SAM, analysis of the GABA binding reveals the presence of binding sites with high affinity, a property absent in control membranes preincubated without SAM.

Perhaps this means that membrane methylation is required to activate GABA receptors?

 

[Solipsis]

It sounds like:

• maybe the extent to which the membrane is methylated at some set of sites is a natural equilibrium regulated by some endogenous analogue to SAMe (or of course SAMe itself), by itself or in entire cascade of effects and artificially administered SAMe would upset this balance in favor of the methylated species.
• The methylated form of membrane phospholipids is energetically favorable to the excited state of GABA receptors in comparison.

But that doesn't necessarily mean that there is ever any endogenous methylation happening to necessarily and immediately serve the activation of GABA receptors. Just that there is this way to enhance it with something like SAMe.

 

[phactor]

I have taken benzos and other gaba drugs both on and off SamE and never really noticed a difference. Obviously not a scientific answer, but that is my personal experience.

 

[Tork]

SAM-E (or SAMe) seems to interact very strange with Phenibut. I took 400mg of SAMe since one week. And today I took 500mg of Phenbiut which is normally barley noticable for me.
A few hours later I got very dizzy and sleepy. Not really uncomfortable but not what i exspected.