Re: Fallon / glutamate->NMDA receptor + abx = Goldstein response

June 22, 2005

" ...has patients that relapse rapidly off Rocephin; too rapidly to be

accounted for by a rebound in bacterial population...

....Lyme activists need to use the Nature paper to their own advantage,

and not have it used against them. But that can't happen until we get

clear on the extent to which Rocephin is palliative vs. curative. "

------------------------------------------------

Matt,

You make some very valid points. In this response I have tried to

explain complex concepts in as simple a way as possible...not for your

sake (you've forgotton more biology than I know) but for all of the

sick patients lurking.

Dr. Goldstein was using antibiotics for their

neuropsychopharmacologic effects starting back in the 80's.

It is very encouraging to see that the awareness of abnormal brain

function associated with chronic disease is starting to take hold.

The use of substances like abx to modulate brain activity should not

be looked at as an either/or proposition. Like everything else

concerning these chronic illness's, it's just not that simple.

Using Rocephin (and all 140+ other substances used in the Goldstein

technique of 'chemical acupuncture of the brain') as a nuero modulator

can be both palliative AND curative for some individuals, depending

upon genetic make-up and the type and duration of illness.

Many infections can produce an immunnologic cytokine response which

alters the brain's control of the immune system. And for those

(usually the one's with younger, stronger immune systems) who's

infection is small and not well entrenched, just these drugs ability

to 'hit the re-set switch' on the brain's control of their immune

system allows their now correctly functioning immune system to

eliminate the infection.

In addition, there are those patients who just have a brain deficit at

the heart of the problem, either a result of genetics (like the Aussie

study of CFS patients which found a genetic flaw in the area that has

to do with the production of cortisol) or possibly childhood abuse. Of

course, all of the above leads to chronic problems of altered immune

response, glutathione depletion...on and on.

Incidently, low glutathione levels in the brain could be contributing

to the problem of increased glutamate toxicity. From Dr. G's most

recent book (In these excerpts Dr. G will refer to the NMDA receptor

(and many others), it is one of the primary receptors for the

exicitatory amino acid (EAA) neurotransmitter glutamate):

------------------------------------

" Glutathione has been used by some physicians as a treatment for CFS.

If this treatment is effective, on way that it might work is by

reacting with nitric oxide to form S-nitrosoglutathione (GSNO) which

interacts with binding sites for glutamate and also binding sites for

some NMDA and AMPA antagonists. Other forms of glutathione are also

effective in blocking the binding of glutamate receptors. Oxidized

glutathione (GSSG) stimulates the binding of dizocilpine, an

NMDA-recptor antagonist. "

------------------------------------

More often (imo) the 'Dr. G style' treatment result is just pallative,

but when the Dr. is faced with the statement " If you don't make me

feel better I'm going to commit suicide " as Dr. Goldstein was a few

times each month, 'only pallative' is not such a bad result.

Until you have personally felt how powerful the result of one of these

'pallative' treatments can be, you will not believe it. A fine example

of this is Penny's response to olmesartan. She experienced a great

deal of symptom relief within no more than a few hours (I recall her

self description in a post on the original I & I board because as soon

as I read it I backchanneled her and told her imo she was experiencing

a 'Goldstein reaction'). The purported mode of action for this

substance is to block the AII receptors which supposdly takes up to 48

hours...meaning that after 90 minutes of the drug being available in

her blood (120 minutes after taking the first pill) only 1/32 of the

receptors would be blocked. Yet she was experiencing major symptom

relief at the same time the drug was only reaching the 3% efficiency

level. As for how or why it worked for her, that is not so clear cut,

From Dr. G's latest book (Tuning the Brain):

---------------------------------------------

" Once in a while, patients will feel sympotmatically improved after

taking an ACE inhibitor or an AII antagonist. Lactate can induce panic

attacks in panic-prone patients. Angiotensin II, when infused into the

dorsomedial hypothalamus, has very similar effects. Injecting the

GABAa agonist muscimol into the dorsomedial hypothalamus blocks both

lactate and AII induced panic attacks...An efferent projection of the

dorsomedial hypothalamus is the bed nucleus of the stria terminalis,

which also transduces events occuring in the medial preoptic area, an

area of major importance in these disorders "

--------------------------------------------

I also recall reading in one of his books that ACE is one of only two

enzymes that degrade substance P (the pain neurotransmitter).

Substance P has been found to be elevated in the CSF of FMS patients,

so there could be a connection there, also.

As for your comment:

" patients that relapse rapidly off Rocephin; too rapidly to be

accounted for by a rebound in bacterial population. "

The inverse of the above scenario is true also, that upon the first

dose patients can feel better within 30-40 minutes...well before any

great reduction in bacterial population.

And when you say:

" Rocephin may indeed

> be palliative by way of glutamate transport, but at least this

> demonstrates glutamate toxicity in patients that had been

> otherwise shunned by the medical community. That is, those in

> the medical establishment who shun sick people can not use

> the Nature paper to undermine the LLMDs that these patients

> turn to with out simultaneously acknowledging the glutamate

> toxicity occuring within the patients they (the conventional

> doctors) have abandoned. "

That is Right On the Money!! It will take a lot of education of the

'conventional' doctors before they understand enough neurology to see

the significance of your words...but compared to 10 years ago, the

research on this field is coming fast and furious.

Here are some more excerpts concerning the nuero effects of

antibiotics, again from Dr. G's recent book. In these he will refer to

the NMDA receptor (and many others), it is one of the primary

receptors for the exicitatory amino acid (EAA) neurotransmitter

glutamate. As a doctor trying to relieve suffering, he found it more

efficacious to target the NMDA receptor first. In other words,

chemical acupunture of the NMDA receptor (and other receptors) can

greatly reduce the glutamate toxicity for some patients:

--------------------------------------

" Almost all antibiotics appear to have psychotropic functions...the

neuropsychopharmacologic effect of most antibiotics is as GABA

antagonists. They may have drug interactions with agents more commonly

regarded as psychotropic. The prototypical antibiotic for inhibition

of the synaptic activity of both the GABAa and the GABAb receptors is

penicillin...

...the cephalosporins and other beta-lactam agents antagonize GABA,

as do the aminoglycosides...(which) activate the N-methyl-D-aspartate

(NMDA) receptor at the polyamine site. This property is dissociable

from their antibiotic activity and may be responsible for vestibular

and cochlear toxicity (Harvey SC et al., 2000).

Oseltamivir phosphate (Tamiflu) is proving to be a useful agent in

treating neurosomatic disorders. Its only known model of action is

inhibiting viral neurminidase, but many patients find that it makes

them feel more alert.

Some antitubercular agents are MAOIs, e.g., isoniazid, or INH. INH

can have an excitatory effect on the central nervous system causing

apprehension, excitement, tremor, and seizures by lowering levels of

GABA through inhibition of the enzyme responsible for GABA synthesis:

L-glutamate decarboxylase. This enzyme requires the active form of

vitamin B6, or pyridoxine, as a coenzyme.

I have not had occasion to use rifampin therapeutically in

neurosomatic patients since its main side effect is on liver

drug-metabolizing enzymes. I prescribe cycloserine (Seromycin)

frequently since it is a partial agonist at the glycine coagonist site

of the NMDA receptor...

...Pentazocine (Talwin) also may reverse the action of NMDA

antagonists and decrease 5-HT (serotonin) and DA (dopamine) activity

(Takahashi S et al., 1999). Chronic administration of a glycine

partial agonist can alter the expression of NMDA receptor subunit

mRNAs (Bovetto S et al., 1997). I know of no other therapeutic

technique to alter subunit expression of any receptor...

....The macrolides include calrithromycin, erythromycin,

troleandomycin, and azithromycin. Biaxin (clarithromycin) is the one

that I have chosen to put on my treatment list since it is well

tolerated. It appears to have a GABA antagonist effect and has the

potential so stimulate the brain motilin receptor...

...Quinolones have had many adverse neuropsychiatric reactions

reported in association with their administration, and it has been

suggested that the CNS excitation seen with quinolones is a result of

displacement of GABA from its receptors. When investigating the

dynurenic pathway of tryptophan metabolism, one sees that quinolones

are a major end product of the dynurenic acid shunt which begins with

tryptophan...

...Agitated depression and atypical postpartum psychosis as well as

panic attacks have been reported with the use of metronidazole...

...The primary exception to most antibiotics (and acyclovir) being

GABA antagonists is found with tetracycline and minocycline but not

with doxycycline and others of the group. The tetracyclines may have

an effect similar to lithium. Antiemetic and antidepressant effects

appear to be associated with tetracyclines (Sternbach H, State R,

1997). Tetracylines, particularly minocycline, are NMDA-receptor

antagonists and often have that effect 30 minutes after

administration. Both minocylcline and tetracycline, but not

doxycycline, can block NMDA-induced exicitotoxicity by inhibiting

NMDA-induced increases in [Ca2+], most likely via a direct action with

the NMDA receptor itself. "

---------------------------------------

The studies of brain abnormalities associated with chronic long term

illness (CFS, FMS, MS...lyme and many others) should be regarded as

further evidence of real, physiological based illness. The spect scans

of lyme patient's brains released last year in an NIH study were

nearly identical to the one's Dr. G did with BEAM (pre spect, mine was

done in 1989) and later spect and functional MRI.

Dr. G made a presentation at the NIH around '93 explaining his theory

of 'a misperception of information salience with resultant

inappropriate allocation of attentional resources by the brain' and

showed how the areas seen affected on the scans supported this theory

( " It took about 5 minutes for their eyes to glaze over " I remember him

telling me, ggg).

As I have said before, my own opinion is that the inappropriate brain

functioning is actually an inherited, pre-conditioned " hibernation

response " as a result of the immune system discovering a infection.

Like the 'fight or flight' stress response. Almost all of

our ancestors lived in small family or tribal units, and I see the

'hibernation response' as a survival strategy for both the group (high

priority) and the individual (low priority). The families that had the

best chance of survival were those who's members, when sick with a

contagion, isolated themselves from the rest of the group.

The very symptoms that we are burdened with;

light sensitive with muscle weakness and pain, fatigue, no appetite or

sex drive...

These 'pains' are the enforcers of isolation, the protectors of group

survival. We should not be amazed at just how debilitating these

symptoms are, they are the result of many generations of our families

surviving the plagues and other ravages of living in an environment

full of creatures that like to make us their home.

The difference between then and now is that now we are saddled with

these symptoms chronically, whereas our ancestors either got well or

died within weeks. And as the years wind on, we accumulate more

symptoms that are not part of the 'hibernation response', but picked

up as a result of inactivity and compromised immunity.

To make a long story short, when I see a brain scan that shows

hypoperfusion of the dorsolateral prefrontal cortex, I see that as

evidence of an infection produced inflammatory immune response, with a

good chance that there is a genetic flaw acting as a catalyst to keep

one's brain in what today (thanks to abx, there are very few life

threatening contagions around) is an inappropriate feedback loop.

The above discussion of antibiotics reveals the ways in which for some

folks abx's may interfere with the brain's inappropriate functioning,

and relieve some patients of most of those symptoms associated with

the 'hibernation response'. The curative, final solution for most of

us will be to follow Tony and Barb's lead of finding out what

infections we are saddled with and the best way to eliminate them

while using nutritional and lifestyle strategies designed to help

overcome any likely genetic defects and/or results of long term

illness (like the dreaded couchpotatoatosis).

Jerry

>

> > Geez. I really don't have the energy to be called to task and

> asked

> > to reproduce an entire conversation and besides I can't do that.

>

> I asked you to clarify the meaning of that portion of the

> conversation which you paraphrased to us. You referred to the

> rapidity with which Dr. Fallon's patients relapse following the

> discontinuation of Rocephin.

>

> You said,

>

> " Fallon seems to think (in conversation/interview) that

> patients may relapse so rapidly off rocephin because.... "

>

> So I asked you,

>

> " So I just want to clarify: he's not now saying that all his Lyme

> patients relapse rapidly following cessation of Rocephin, is he? "

>

> Since you are the one who talked to him about the rapidity with

> which his patients relapse following the discontinuation of

> Rocephin, I am asking you if he gave you some idea about the

> incidence of this problem. Do most of his patients relapse

> rapidly, or is this relatively uncommon?

>

> > Please refer to the Nature paper. I have nothing to clarify.

>

> The Nature paper did not report on how Dr. Fallon's patients

> respond to Rocephin. You did. That is why I asked you to clarify

> what you meant.

>

> It took only a couple of months for the NEJM to use the Nature

> paper to take a shot at Lyme activism (see my post #1328). The

> NEJM article states that the benefits that are seen with the use of

> Rocephin are being used by some people as evidence that

> certain patients indeed have Lyme. But the NEJM article uses

> that Nature paper to undermine that argument. Now you are

> reporting that Dr. Fallon has patients that relapse rapidly off

> Rocephin; too rapidly to be accounted for by a rebound in

> bacterial population.

>

> You appear then, by way of Dr. Fallon, to be lending weight to the

> NEJM's position.

>

> That's OK. But the next question is: how much credibility will

> Lyme patients lose if they do not address this issue proactively?

> A good fall-back position is for patients/LLMDs to say that, in

> accordance with the Nature paper and the criticism of Lyme

> activism that appears in the NEJM article, Rocephin may indeed

> be palliative by way of glutamate transport, but at least this

> demonstrates glutamate toxicity in patients that had been

> otherwise shunned by the medical community. That is, those in

> the medical establishment who shun sick people can not use

> the Nature paper to undermine the LLMDs that these patients

> turn to with out simultaneously acknowledging the glutamate

> toxicity occuring within the patients they (the conventional

> doctors) have abandoned.

>

> Lyme activists need to use the Nature paper to their own

> advantages, and not have it used against them. But that can't

> happen until we get clear on the extent to which Rocephin is

> palliative vs. curative.

>

> Matt

June 22, 2005

Wow I think this may be the first post of yours I've read but that

was completely fascinating. I don't even know who Goldstein is or who

you are but I'm going to email myself this post.

YOu know some biotechs are working on the tetracycline class to sift

out simply the immunomodulating properties. I guess thats worthwhile.

THey'll be non antibiotic antibiotics.

Personally I agree with your end statement about, find the infection,

then the brain can reset itself.

And definitely there are genetic predispositions.

This makes me wonder more than ever what hyperbaric oxygen does and

why it is so helpful to me, in addition to making my blood such a

pretty bright red color .

> >

> > > Geez. I really don't have the energy to be called to task and

> > asked

> > > to reproduce an entire conversation and besides I can't do that.

> >

> > I asked you to clarify the meaning of that portion of the

> > conversation which you paraphrased to us. You referred to the

> > rapidity with which Dr. Fallon's patients relapse following the

> > discontinuation of Rocephin.

> >

> > You said,

> >

> > " Fallon seems to think (in conversation/interview) that

> > patients may relapse so rapidly off rocephin because.... "

> >

> > So I asked you,

> >

> > " So I just want to clarify: he's not now saying that all his Lyme

> > patients relapse rapidly following cessation of Rocephin, is he? "

> >

> > Since you are the one who talked to him about the rapidity with

> > which his patients relapse following the discontinuation of

> > Rocephin, I am asking you if he gave you some idea about the

> > incidence of this problem. Do most of his patients relapse

> > rapidly, or is this relatively uncommon?

> >

> > > Please refer to the Nature paper. I have nothing to clarify.

> >

> > The Nature paper did not report on how Dr. Fallon's patients

> > respond to Rocephin. You did. That is why I asked you to

clarify

> > what you meant.

> >

> > It took only a couple of months for the NEJM to use the Nature

> > paper to take a shot at Lyme activism (see my post #1328). The

> > NEJM article states that the benefits that are seen with the use

of

> > Rocephin are being used by some people as evidence that

> > certain patients indeed have Lyme. But the NEJM article uses

> > that Nature paper to undermine that argument. Now you are

> > reporting that Dr. Fallon has patients that relapse rapidly off

> > Rocephin; too rapidly to be accounted for by a rebound in

> > bacterial population.

> >

> > You appear then, by way of Dr. Fallon, to be lending weight to

the

> > NEJM's position.

> >

> > That's OK. But the next question is: how much credibility will

> > Lyme patients lose if they do not address this issue

proactively?

> > A good fall-back position is for patients/LLMDs to say that, in

> > accordance with the Nature paper and the criticism of Lyme

> > activism that appears in the NEJM article, Rocephin may indeed

> > be palliative by way of glutamate transport, but at least this

> > demonstrates glutamate toxicity in patients that had been

> > otherwise shunned by the medical community. That is, those in

> > the medical establishment who shun sick people can not use

> > the Nature paper to undermine the LLMDs that these patients

> > turn to with out simultaneously acknowledging the glutamate

> > toxicity occuring within the patients they (the conventional

> > doctors) have abandoned.

> >

> > Lyme activists need to use the Nature paper to their own

> > advantages, and not have it used against them. But that can't

> > happen until we get clear on the extent to which Rocephin is

> > palliative vs. curative.

> >

> > Matt

June 22, 2005

Gerry, thanks for that. Fascinating. Funny, as I was reading along,

I was thinking to myself, " yeah, that could be what's happening to

me with Benicar " and then there it was in black and white...even Dr.

G agreeing.

Yes, I think that Benicar is somehow suppressing both my pain

response, AND my anxiety levels. I've never had overt anxiety or

panic attacks, but looking back, I realized that I always felt very

stressed, always on very high alert. Like constantly ready for fight

or flight (more emphasis on flight - not so much fight - although I

always had a strong aversion to injustice and could get myself

pretty agitated over things that seemed unfair or unethical). I

think that's why the simplest of activities could make me absolutely

exhausted afterwards. I never understood why I was so tired and

other people could bounce right back.

These days, I can tell when the Benicar is wearing off, because my

teeth start to lightly chatter (something they've done for decades,

until Benicar), and I think this is an anxiety related symptom.

Whether it has to do with adrenals or what, I don't know, but I do

know that I no longer have the exaggerated stress levels that I did

pre-benicar.

I'm also one of those pwc who reacts adversely to the anti-

depressant zoloft. Makes me extremely anxious, even at very small

doses. (not an uncommon reaction among pwc).

I didn't see on your list the drug family that includes Bactrim, but

I stopped bactrim when I began to experience hallucinations. They

only happened when I closed my eyes, but they were becoming more and

more psychedelic and frequent, and I got nervous and afraid it was

going to become a bigger problem (like when my eyes were open), so

stopped.

So yeah, I think the brain is definitely involved in our illness and

our response to treatment. In more ways than one. I always said

Cipro, my first serious attempt at abx, gave me my brain back. The

fog lifted (and very quickly).

The way I can tell if an ABX is helping me is threefold. Reductions

in fatigue, brain fog, and jaw pain. Whether that's due to bugs

being killed I don't know for sure, but CT scans of my sinuses

before and after seem to support the theory that not only do I feel

better on those abx, but the bugs are being killed too. But I also

know that many of us with a particular focal infection in the jaw

(that we can feel), notice a reduction in pain or pressure very

quickly when we take the right abx, which has always puzzled me. Is

it a reduction of bacterial numbers that occurs so quickly, or

something else? But when the abx wears off, the pain or pressure

comes back. However, in my case anyway, so does the salty taste that

accompanies it, which is a sign of actual bacteria, either

actinomyces or staph aureus. So it seems the bacteria is also being,

at the very minimum, suppressed somehow.

I think your hibernation theory makes some sense too. I've always

felt that the fatigue was our bodies way of slowing us down. Happens

when you get any short term bug. You just want to go to bed. The

hibernation theory is a logical extension of the body not only

protecting itself, but it's community as well.

Dr. Goldstein was one of the first people I researched when I was

first dx'd with CFS. I remember trying to talk about him to other

pwc. Back then, I think he actually used the term " psychosomatic "

rather than " neurosomatic " and even though he explained in detail

that this is a real illness, not a " mental one " , most people would

get all up in arms every time I tried to broach the subject. I

eventually decided, after speaking with a few people that had been

treated by him, that his results were often short lived (but who

knows, if I'd gone to see him years back, perhaps I'd have been on

an arb much sooner?). At the same time, I started becoming aware of

the infection angle, so dropped the neurosomatic focus, but I still

thought he did a lot of really good work.

I showed my doc Dr. G's statement about " curing " mononucleosis with

cimetidine, and he was REALLY interested. It's a shame people have

ignored his many contributions because they're afraid he's talking

about mental illness, rather than neuro involvement.

penny

> >

> > > Geez. I really don't have the energy to be called to task and

> > asked

> > > to reproduce an entire conversation and besides I can't do

that.