Deprenyl's l-amphetamine metabolites
Steve Farmer
It has been argued by CERI's supporters that the amphetamine
metabolites of deprenyl are innocuous since they are "l" isomers.
This claim is incorrect.
D-amphetamine and l-amphetamine do have important differential effects
in different tissues. For example, d-amphetamine works 5-10 times more
strongly (according to different studies) than l-amphetamine in some
brain tissues where norepinephrine-containing neurons dominate. But in
tissues where dopamine neurons dominate, the "d" and "l" isomers of
amphetamine are often of roughly *equal* strength. Most importantly,
this is true in the corpus striatum, which is part of the brain
adversely affected by Parkinson's disease. In the corpus striatum,
l-amphetamine and d-amphetamine are *equally* active in blocking
catecholamine uptake.
This fact is what has repeatedly led Parkinson's researchers to
suggest that parts of deprenyl's therapeutic and/or toxic effects may
derive from the drug's l-amphetamine and l-methamphetamine
metabolites. To represent these metabolites as innocuous since they
are "l" and not "d" isomers is a distortion.
Abstracts from two papers are provided below in evidence. The first is
the classical paper by Taylor and Snyder that first raised these
issues. The second discusses the equality of strength of "l" and "d"
amphetamine isomers in the neuroendocrine system. Other studies
discuss the powerful effects of "l" as well as "d" amphetamine and
methamphetamine in other brain regions.
**************
Science 168: 1487-1489 (1970)
Amphetamine: Differentiation by d and l isomers
of behavior involving brain norepinephrine or dopamine
K. M. Taylor and S. H. Snyder
d-Amphetamine is markedly more potent an inhibitor of catecholamine
uptake by norepinephrine neurons in the brain than is l-amphetamine,
whereas the two isomers are equally active in inhibiting catecholamine
uptake by the dopamine neurons of the corpus striatum. In behavioral
studies, d-amphetamine is ten times as potent as l-amphetamine in
enhancing locomotor activity, while it is only twice as potent in
eliciting a compulsive gnawing syndrome. This suggests that the
locomotor stimulation induced by amphetamine involves central
norepinephrine, while dopamine neurons plan an important role in the
induced compulsive gnawing behavior. Assessment of differential
actions of d- and l-amphetamine may be an efficient method to
differentiate behaviors involving norepinephrine or dopamine in the
brain.
***************
Endocrinology 99: 459-65 (1976)[76257040]
Cortisol and GH responses to D- and
L-amphetamine in monkeys.
R. Marantz, E. J. Sachar, E. Weitzman & J. Sassin
Equimolar doses of D-amphetamine and L-amphetamine, and a water
placebo were injected intravenously on different days into rhesus
monkeys,
and their plasma cortisol and GH responses were determined over a 3-hour
period. D- and L-amphetamine (but not the placebo) equally suppressed
plasma cortisol concentration and equally increased plasma GH
concentration. Pretreatment of the monkeys with large doses of pimozide,
a specific dopamine receptor blocker, did not appear to block the
hormonal responses to either isomer of amphetamine. The results
suggest that the hormonal responses to both D- and L-amphetamine were
mediated by noradrenergic neurones stimulatory to GH and inhibitory to
ACTH, and that D- and L-amphetamine exert equipotent noradrenergic
effects in the neuroendocrine system.
Daniel R Haney
re: compulsive/stereotypic behavior from amphetamine use
IN HUMANS -
These behaviors usually manifest at higher (= abusive)
doses of amphetamines and are pretty characteristic where
the user compulsively does the same thing repetitively.
Oddly, when asked about it, the same users often say they
don't even like doing it, yet continue.
When Sweden had an amphetamine abuse problem in the 50's,
that is, a whopping 0.4% of the population was using ONE drug,
researchers saw the above abuse-level behavior so often they
had to give it a name: "punding."
How does this relate to lower dose levels where the
compulsive/stereotypic behavior DOES NOT manifest?
Daniel r. Haney
Steve Farmer
Daniel R. Haney writes, re compulsive/stereotypic behavior from
amphetamine use:
> These behaviors usually manifest at higher (= abusive)
> doses of amphetamines and are pretty characteristic where
> the user compulsively does the same thing repetitively.
> Oddly, when asked about it, the same users often say they
> don't even like doing it, yet continue.
>
> When Sweden had an amphetamine abuse problem in the 50's,
> that is, a whopping 0.4% of the population was using ONE drug,
> researchers saw the above abuse-level behavior so often they
> had to give it a name: "punding."
>
> How does this relate to lower dose levels where the
> compulsive/stereotypic behavior DOES NOT manifest?
>
You're punding around with these objections, Daniel. Actually, the
animal studies show stereotypical behavior at various doses, from both
l-amphetamine and d-amphetamine. Here is a scrap of evidence from
another study:
Science 190: 475-7 (1975)[76033765]
Behavioral characterization of d- and
l-amphetamine: neurochemical
implications.
D. S. Segal
Various doses of d- and l-amphetamine affect the temporal pattern of rat
behavior in the following ways: First, the patterns of activity produced
by d- and l-amphetamine are similar but out of phase; that is, the
response to d-amphetamine has a relatively shorter latency whereas the
effects of l-amphetamine persist for longer periods of time. Second,
d-amphetamine is approximately five times as potent as l-amphetamine in
its effects on both the total amount of locomotor activity and the
duration of stereotypy. Both amphetamine-induced locomotion and
stereotypy may be mediated by the same neurochemical mechanisms.
My best,
Steve Farmer
Daniel R Haney
In sci.life-extension you write:
>Daniel R. Haney writes, re compulsive/stereotypic behavior from
>amphetamine use:
>> These behaviors usually manifest at higher (= abusive)
>> doses of amphetamines
>> ...researchers saw the above abuse-level behavior so often they
>> had to give it a name: "punding."
>>
>> How does this relate to lower dose levels where the
>> compulsive/stereotypic behavior DOES NOT manifest?
>>
>You're punding around with these objections, Daniel. Actually, the
>animal studies show stereotypical behavior at various doses, from both
>l-amphetamine and d-amphetamine. Here is a scrap of evidence from
>another study:
>Science 190: 475-7 (1975)[76033765]
>Behavioral characterization of d- and
>l-amphetamine: neurochemical
>implications.
Steve,
You think _that_ was punding? *I'll* show you punding!
By gawd, when I'm through, you'll be careful whom *you*
indict for punding. You really don't know punding as
I know punding, but you're about to get a dose of punding
you...you...
Another gibbering example of inarticulate 'punding' follows:
"And they went and they went and they went and they went and they went
and they went and they went and they went and they went and they went
and they went and they went and they went and they went and they went
and they went and they went and they went and they went and they went
and they went and they went and they went and they went and they went..."
from "Crankenstein", an unpublished novel
by Frederick "Fat Freddy" Freekoutski
(nom de plume of Gilbert Sheldon)
Compulsive actions differ from punding in the same
way that a tape loop differs from the phono stylus
stuck in a groove at 78 rpm - it is a matter
of acute degree.
BTW, I heard that the current crop of Meth-heads call it
"tweaking."
Hmpf. I like the Swedish one better.
Now, your citation re: l-amphetamine promoting compulsive
gnawing behavior (punding) in rats is significant. But punding
only manifests at the higher doses. You consistently cite stuff
on pathological behaviors at the high end of the dose spectrum.
What gives? I see a recurrent logic error here:
"The worst case is the normal case"
You may well be correct in this, but I'm deeply suspicious of
this kind of logic because it is in such common use by an
insufficiently accursed sub-subspecies known as politician.
Redundantly, I reiterate one more time again:
What happens at low doses (1-2mg) of deprenyl? I am
skeptical of assertions about grave toxicity at that level.
Unconvinced but raptly listening,
Daniel R. Haney
Steve Farmer
Daniel R. Haney wrote:
> Now, your citation re: l-amphetamine promoting compulsive
> gnawing behavior (punding) in rats is significant. But punding
> only manifests at the higher doses. You consistently cite stuff
> on pathological behaviors at the high end of the dose spectrum.
> What gives? I see a recurrent logic error here:
The paper referred to stereotypical behaviors at various dose levels.
We know from studies of amphetamine-like drugs that pathological
behavior can indeed sometimes be triggered by very small doses. But
for the sake of argument, Daniel, I'll agree that you weren't punding
- just gnawing.
Daniel wrote:
> Redundantly, I reiterate one more time again:
>
> What happens at low doses (1-2mg) of deprenyl? I am
> skeptical of assertions about grave toxicity at that level.
I'm equally skeptical of assertions that toxicities at that level
*don't* exist. When a drug is toxic at 10 mg, the burden of proof lies
on the shoulders of the drug *proponent* to demonstrate that it
*isn't* toxic at lower doses.
Dose response curves of drugs affecting the catecholamine pathway are
non-linear and may change radically with chronic use. 1/10th of a dose
of a toxic drug doesn't necessarily mean 1/10th the toxicity.
Sometimes a 22 caliber bullet can kill you as surely as a cannon.
My best,
Steve