IUBio

...

John H. John at faraway.com.au
Fri Oct 12 06:38:21 EST 2001


Liar42

Yes, my concern with LSD was a sad experience at a party many years ago. A
young chap was there, about 18 years old, who I had not met before but
struck me as acting rather oddly. After a while someone who had known this
chap for many years asked someone there, "What's wrong with him, he seems
different?"
 The reply: "He went to Melbourne for two weeks and dropped acid everyday,
hasn't been the same since."

Apart from that though, I had no warrant to claim that LSD causes brain
damage, rather operating on rather broad assumptions (that anything that
increases brain activity over a long time is often causing cell death) and I
do not know of any evidence to clearly demonstrats LSD causes brain damage.
Timothy Leary may have been alive and kicking to a good old age and so to
Hoffman but you might want to consider that these were also two rather
knowledgeable men who took the appropriate measures. They didn't just take
the drugs, they probably (well, with Leary after the initial craziness ... )
were much more careful than your average Joe or Jill in taking steps to
minimizing the potential bad effects of the drug.

Ecstasy. Lots of people are warning about the brain damage that follows
sustained ecstasy use. This is not news, you don't have to believe me,
enough research has been done. Here's a couple:

Extract from below article notes, Molecular Mechanism of the Inactivation of
Tryptophan Hydroxylase by Nitric Oxide: Attack on Critical Sulfhydryls that
Spare the Enzyme Iron Center
:

Selected amphetamines have profound effects on the 5-HT neuronal system.
Methylenedioxymethamphetamine (ecstasy) (MDMA) and p-chloroamphetamine cause
extensive destruction of 5-HT neurons
...
The recent demonstration that TPH is inactivated by NO in vitro (Kuhn and
Arthur, 1996, 1997) establishes the possibility that this important brain
enzyme is susceptible to inactivation by NO in vivo and could form the basis
for loss of TPH activity when NO levels are elevated in brain (e.g.,
amphetamine-induced).

-----

And the other two items below that article clearly demonstrate the dangers
of ecstasy. Also, note the year of this research. This is not news, but I
have noticed that many people using ecstasy still fail to appreciate the
reality of the dangers.

Yes, drugs do sometimes help people see other points of view or come to new
understandings. I have seen an interview with a Nobel Prize winner who
stated he found the solution on an acid trip, and there is evidence here and
there that individuals have made major discoveries with a little help from
their friends. However, there are many preconditions which made such
discoveries possible, and usually the individuals were not regular users of
the drugs; often having a strict discipline about the use of the drugs to
aid their work. Anecdotally, it does seem to me that particularly
intelligent people are more prone to drug abuse, I have known some brilliant
alcoholics. I don't understand that.

Additionally, these are the types of people who often do enough homework to
find out to minimize any possible ill effects. There are strict limits to
that though, no amount of Vit E etc will stop all the damage. What worries
me is that today many people are using these drugs in complete ignorance.
The new class of drugs like GBH, which are very potent and potentially very
destructive, should be a major public health concern. I just want people to
know what they are letting themselves in for.

As to the metaphysics, enough said ...  so in some vague sense I have an
appreciation for your feelings re non verbal images of the universe. One of
my favourite signposts in that regard is this quote from Metaphoric Process:
The Creation of Scientific and Religious Understanding, Gerhart & Russell,
"We can see then, that religious and scientific ideas differ in the
frequency with which they point beyond themselves."

There's nothing wrong with thinking about questions that cannot be addressed
in an 'empirical' way. Probably essential, as Wittgenstein notes, "It seems
to us that when all the scientific questions have been answered the truly
important questions about life remain untouched." In these days at least,
most of the time(in spite of listening to Joy Division too often), I run
with the advice of the physicist Feynman when he said that it is important
to address questions that can be answered, to avoid addressing questions
that can never be finally answered.

Acid,

No, my last trip, nearly a decade ago now, was fun. I just lost interest.

You do raise interesting questions.

Regards,

John H.


Article: Molecular Mechanism of the Inactivation of Tryptophan Hydroxylase
by Nitric Oxide: Attack on Critical Sulfhydryls that Spare the Enzyme Iron
Center
Authors: Donald M. Kuhn 1,2 and Robert Arthur Jr 1
Journal: The Journal of Neuroscience, October 1, 1997, 17(19):7245-7251
Location:
N\Ni
NOS inhibits serotonin via tryto hyrodrox
Date obtained: 31/01/00
Web Page:
Date Read: 27/02/00
Date to Review: 15/10/00
Keywords:
Key words: tryptophan hydroxylase; nitric oxide; sulfhydryls;
catalytic iron site; serotonin; neurotoxic amphetamines, nos, flf, ros,
aspartmane,
ecstasy, mdma, 5ht neurons, depression,
Printed:
No = subject: 1
Notes:
Tryptophan hydroxylase (TPH), the initial and rate-limiting en-zyme in the
biosynthesis of the neurotransmitter serotonin (5- HT), is irreversibly
inactivated by nitric oxide (NO). We have expressed brain TPH as a
recombinant glutathione-S-transferase fusion protein and delineated the
catalytic domain of the enzyme as the region spanning amino acids 99-444.
Highly purified TPH catalytic core, like the native enzyme from brain, is
inactivated by NO in a concentration-dependent man-ner. Removal of iron from
TPH produces an apoenzyme with low activity that can be reconverted to its
highly active holo-form by the addition of ferrous iron. Apo-TPH exposed to
NO cannot be reactivated by iron. Treatment of holo-TPH (iron-loaded) with
the disulfide 5,59-dithio-bis (2-nitrobenzoic acid) (DTNB) causes an
inactivation of TPH that is readily reversed by dithiothreitol (DTT).
DTNB-treated TPH [sulfhydryl (SH)-protected] exposed to NO is returned to
full activity by thiol reduction with DTT. The inactivation of native TPH by
NO cannot be reversed by either iron or DTT. These data indicate that NO
inactivates TPH by selective action on critical SH groups (i.e., cysteine
residues) while sparing catalytic iron sites within the enzyme. The results
are interpreted with reference to the substituted amphetamines, which are
neurotoxic to 5-HT neurons, that inactivate TPH in vivo and are now known to
produce NO and other reactive oxygen species in vivo.
--
Selected amphetamines have profound effects on the 5-HT neuronal system.
Methylenedioxymethamphetamine (ecstasy) (MDMA) and p-chloroamphetamine cause
extensive destruction of 5-HT neurons. An early manifestation of their
effects is a significant inactivation of TPH (for reviews, see Gibb et al.,
1993; Steele et al., 1994; Seiden and Sabol, 1996). The mechanisms
underlying these effects on TPH are not known, but emerging data implicate
drug-induced production of reactive oxygen species (ROS) and nitric oxide
(NO). The cellular effects of ROS or NO cannot be predicted a priori: NO can
be toxic to some cells (Lipton et al., 1993; Dawson et al., 1994), it is a
neurotransmitter- neuromodulator in other cells (Jaffrey and Snyder, 1996),
and it can protect still other cells from known toxins (Wink et al., 1995,
1996). The recent demonstration that TPH is inactivated by NO in vitro (Kuhn
and Arthur, 1996, 1997) establishes the possibility that this important
brain enzyme is susceptible to inactivation by NO in vivo and could form the
basis for loss of TPH activity when NO levels are elevated in brain (e.g.,
amphetamine-induced).
--
 By altering independently the iron or SH status of TPH, we demon-strate
that NO inactivates TPH by selective attack on critical SH groups, sparing
catalytic iron sites altogether.
--
These experiments establish the importance of iron in TPH f unc-tion and
demonstrate that TPH can be reversibly converted be-tween the apo- and
holo-forms.
--
The present results lead to several interesting conclusions about TPH.
First, they reaffirm the importance of iron and SH groups (free cysteines)
in TPH catalytic f unction. Second, they establish the feasibility and value
of using highly purified, recom-binant TPH to probe the molecular mechanisms
regulating this enzyme. Finally, they point to SH groups as targets for
NO-induced inactivation of the enzyme.
-------------

16/12/98 22:04

Adverse neuropsychiatric events associated with dexfenfluramine and
fenfluramine.

McCann UD, Eligulashvili V, Ricaurte GA
Biological Psychiatry Branch, National Institute of Mental Health, Bethesda,
MD, USA.

[Medline record in process]

Positron emission tomographic evidence of toxic effect of MDMA ("Ecstasy")
on brain serotonin neurons in human beings.

McCann UD, Szabo Z, Scheffel U, Dannals RF, Ricaurte GA
Biological Psychiatry Branch, National Institute of Mental Health, Bethesda,
Maryland, USA.

BACKGROUND: (+/-)3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") is a
popular recreational drug that selectively damages brain serotonin (5-HT)
neurons in animals at doses that closely approach those used by humans. We
investigated the status of brain 5-HT neurons in MDMA users. METHODS: We
enrolled 14 previous users of MDMA who were currently abstaining from use
and 15 controls who had never used MDMA. We used positron emission
tomography (PET) with the radioligand carbon-11-labelled McN-5652, which
selectively labels the 5-HT transporter. We analysed whether there were
differences in 5-HT transporter binding between abstinent MDMA users and
participants in the control group. Blood and urine samples were taken and
tested to check for abstinence. FINDINGS: MDMA users showed decreased global
and regional brain 5-HT transporter binding compared with controls.
Decreases in 5-HT transporter binding positively correlated with the extent
of previous MDMA use. INTERPRETATION: Quantitative PET studies with a ligand
selective for 5-HT transporters can be used to assess the status of 5-HT
neurons in the living human brain. We show direct evidence of a decrease in
a structural component of brain 5-HT neurons in human MDMA user

MDMA-induced neurotoxicity: parameters of degeneration and recovery of brain
serotonin neurons.

Battaglia G, Yeh SY, De Souza EB
Neuroscience Branch, National Institute on Drug Abuse, Baltimore, MD 21224.

This study investigates a number of parameters that influence the neurotoxic
effects of 3,4-methylenedioxymethamphetamine (MDMA) on serotonin (5-HT)
neurons in brain. Both the dose and number of injections of MDMA affect the
degree of neurotoxicity on 5-HT axons and terminals as assessed by decreases
in the content of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) and the
density of 5-HT uptake sites. Repeated systemic administration of various
doses of MDMA (5-20 mg/kg twice daily for 4 consecutive days) results in
dose-dependent decreases in 5-HT, 5-HIAA and 5-HT uptake sites. Increasing
the number of injections of MDMA resulted in progressively greater
reductions in 5-HT and 5-HIAA which occurred prior to decreases in 5-HT
uptake sites. In contrast, no significant changes were observed in the
density of norepinephrine uptake sites following single or repeated
injections of 20 mg/kg MDMA. With respect to neuronal regeneration,
following an initial 90% loss of 5-HT uptake sites after treatment with
MDMA, the recovery of these sites occurred over a protracted period of time;
a marked 25% reduction was seen at 6 months and the concentration of 5-HT
uptake sites returned to control levels at 12 months following treatment
with MDMA. Pretreatment with the selective 5-HT uptake blocker, citalopram,
prior to each injection of MDMA prevented the neurotoxic effects of MDMA on
the 5-HT parameters described above suggesting that active uptake of MDMA or
a MDMA-related substance into brain 5-HT neurons was involved in the
neurotoxic actions of the drug. In addition, the neurodegenerative effects
of MDMA on 5-HT neurons exhibited some species specificity as comparable
decreases in cerebral cortical 5-HT, 5-HIAA and 5-HT uptake sites were
observed in rat and guinea pig while no significant changes in any of these
serotonergic parameters were seen in mouse brain.

PMID: 2452449, UI: 88203802

"Liar42" <liar42 at aol.com> wrote in message
news:20011011033336.23196.00000367 at mb-bk.aol.com...
> >(...) I don't regard it as that important either. It would not
> surprise me but unlike many others I'm not prepared to claim to know what
all
> that is about.<
>
> I have some interests in LSD grey magic,
> and there fore a while was to do with energy translinks between some brain
> areas, but where I come from magic seems to be exchanged about more
magically,
> not like a lot of writing like maybe is more found in English, more maybe
like
> Red Indians, where it also seems not custom to write about it (and from
> Aborigines I also did not hear about a lot of writing there)
>
> ... but in many areas there is a lot where I know little to nothing about
such.
>
> > The universe is spooky,<
>
> The bits of it I perceived from here I did not find that spooky,
> not that I wish to exclude that some there spook about / spirit travel
quite
> far, however on Earth I am more familiar with encountering someone sort of
> spooking around, of a dead or living human for example.
>
> (I found a graveyard in Berlin partially spooky.
> Not looking up at the night sky and stars there.)
>
> With the universe what puzzles me is where it ends and what is behind?
>
> I find that one of the most intriguing questions.
>
>
> > Avoid Vitamin C min 3 days before trip because Vit C, contrary to the
popular
> wisdom, is now being shown to have nasty affects in inflammatory states.<
>
> I did not regard vitamin C as a problem so far, to the opposite, sometimes
when
> I wanted to come down a bit I used a drink with a lot of it in there for
that
> purpose (takes about 20 minutes after drinking it for me to come "down"
quite a
> bit more).
>
> Concering the immune system(s) I am generally used that for about 36 h
> "defense" capacities there might go down.
>
> With some "smaller" stuff like rather harmless colds I sometimes even
found
> that rather convenient.
>
> (Sort of once the systems kick back in O.K. then I might be rid of it real
> fast. Simplified alike the intruder made itself more fat than normally it
could
> and afterwards seems easiert to be terminated then.)
>
> > Acid, like ecstasy, induces serotonin
> metabolism, which in turn generates super
>
> anions.<
> ?
>
> > These, in conjunction with
> nitric oxide, generated by glutamingeric activity, will, with super
anions,
> become peroxynitrate,<
>
> I can't follow you well there because I understand too little about
such ---
> though I get the gist.
>
> But I know little to nothing about single groups of such substances and
what
> they do.
>
> > which does really nasty things to cells.<
>
> I can't say that I noticed much about such.
>
> I know alc does kill cells and cocaine seemed to as well.
>
> But with LSD I did not notice alike effects,
> nor have I ever heard before that LSD kills brain cells.
>
> (Not that I'd have problems to rattle down some systems, partially in my
> terminology, that it registered to be bad for.)
>
> > Hence long term abuse of ecstasy killing all those serotongernic cells.<
>
> You are the first one I recall to state that ecstasy kills brain cells,
and if
> they all of those cells you mentioned were really dead how comes that
> ecstasy users, unless not drinking enough, do not hit techno disco floors
dead
> way more often? Or can a human live without these cells, fi they are
really all
> dying?
>
> Anyway, I doubt it kills them all.
>
> I don't even recall the immediate impression that quite a bunch of cells
are
> dying, like with high amounts of alc or with C.
>
> ... But I just took E a few times and partially in combi with something
else
> (and also not always a full tablet).
>
> I heard more rumours that E can alter synaptic connection "patterns" and
that
> it can cause motoric damages, and after I saw someone having twitches in
> between in a disco, who had taken like 4 or 5 Es, I figured that might be
more
> than just some rumour, and did not take it that often also for other
reasons
> than that I do not wish to damage movements steering systems in my brain
too
> much (what I call the sequencer in my brain and me are seeming often
rather
> segregated, and the life also of another person in traffic might depend on
that
> the sequencer does not mess up when I am not driving but leaving such to
it and
> trust it far enough or just linked off without thinking much about such).
>
> > Sustained excessive activity or even short but very intense bursts of
> serotonin metabolism can overwhelm our natural defences,<
>
> How? I had assumed that central immune systems aspects are in the body.
>
> BTW, questions (to anyone who knows and feels like answering): Is the
sternum
> hollow with marrow in the middle?
>
> Is it a bone or more like cartilage?
>
> > so post trip also have good
> carbohydrate<
>
> I am not even sure what foods all have that
> and also a lot of my food selection might have not so much to do with me
(I
> happen to not regard my self as centrally competent for that and figure
other
> systems might understand way more about what is needed than me).
>
> > based meals to boost serotonin synthesis back up, <
>
> I am not so worried about that.
>
> I do not exclude that if there is a too much
> receptor molecules go down,
>
> but I am not so worried about the production.
>
> Also you might overlook that in the times I tended to take LSD about once
a
> week in Berlin I was used to effects of that.
>
> I do not say that they are all comfortable, but there are other negative
> aspects concerning LSD that I tended to regard as more relevant than brain
> stuff.
>
> Apart from that Timothy Leary I heard reached 75 years of age
> and on a picture that a newpaper wrote was his last looked rather merry
and
> content.
>
> So I don't really worry that much, if anything more about kidneys health.
>
> BTW, is Hofmann
> (the "father" of LSD who is said to have taken it still in older age)
> dead and if so  how old was he when he died?
>
> >as the oxidants created will also destroy tryosine hydroxlase, necessary
for
> synthesis.<
>
> As long as not all is /are destroyed
> why should not later more be produced?
>
>
> (Acid ...) > Trouble used to be finding good quality<
>
> Sounds very familiar.
>
> ;-)
>
> > but the thrill wears off pretty quickly.<
>
> It later tended not to be like the first times, but I do not recall one
LSD
> trip that I found boring.
>
> I am still fascinated by LSD.
>
> (Wish I had some here.
> ... Maybe when I'm back to Europe I'll look around for some.)
>
> > Acid use demonstrates how fragile our consciousness of the world
> is: it affects serotonin pathways.<
>
> Acid has many effects in my head & body, and can be used for various
purposes
> in my head, and somehow I regard the consciousnesses in my head like
rather
> differing systems,
> and how much I perceive of the world around, apart from MBD aspects, I
regard
> also very much to do with how interested I happen to be to perceive about
outer
> aspects for a while or shortly in between.
>
> (Not that I say hardware stuff is irrelevant.)
>
> > for me it just made it great fun to watch the fire.<
>
> With the pupils wide I might find that too bright.
>
> (I often prefered akasha surfing. Like energy perception games with
another
> person.)
>
>









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