9 replies to this topic

[flatline]

I have recently begun using Tianeptine (Stablon), Adrafinil (Olmifon), and Selegeline (Deprenyl, or Cyprenyl in particular). The Tianeptine is for when I am in need of an anxiolytic or mood-brightening effect -- I believe this kind of use can be described as acute so I will continue to use the term in this manner. The Adrafinil is for when I need to be more awake, and this is more of a daily thing with weekend Holidays. I am monitoring liver enzyme levels for safety. The Selegeline is a new addition and I would like it for its badly needed motivation inducing effect.

I continue to come across the terms "sensitization," "down-regulation," and "up-regulation" and I recognize that these imply a semi- or fully-permanent alteration of one's neurons. My understanding is that regulation involves an increase or decrease in the amount of a neurotransmitter's receptors, or the rate of production/release of a neurotransmitter. Sensitization seems to be a heightened sensitivity to a substance to the point that it becomes difficult to use for intensity or side-effects.

My concern is the potential for damage from these substances via the aforementioned mechanisms, or any others that I might not be aware of. What is the influence of acute vs. chronic usage of a substance? For example, "Chronic treatment with amineptine induces downregulation of dopamine D2, beta- and alpha 2-adrenergic receptors." [http://www.amineptine.com/aminep.htm] What is the consequence of this, subjectively and physiologically? Is this effect reversible with discontinuation? How is it that down-regulation or up-regulation do not have to correlate with tolerance to a medicine?

I realize that the Psychopharmacology is hazy about a lot of this, but I would very much appreciate any and all help with these questions. Thank you for reading!

[theta]

SSRI's initially flood the brain with serotonin triggering down-regulation of serotonin receptors but after a few weeks
the levels normalize.

Interesting that amineptine down-regulates D2 receptors. That
means it must not inhibit the release of dopamine like Ritalin. I
think drugs like wellbutrin that do inhibit release of dopamine do
not down-regulate D2. D2 agonist quickly down-regulate D2 receptors also. Interesting dangerously high doses of Zocor have been proven to up-regulate D2 receptors in lab animals. Down-regulated or initial low levels of D2 receptors is a proven risk factor for drug and alcohol addiction in people. Other than agonist or abusable drugs I doubt you have a major risk of D2 down-regulation.

[graatch]

>I recognize that these imply a semi- or fully-permanent alteration of one's neurons

No, they don't. Reregulation is a constant process. Stop taking something exogenous and things will get back to normal. Don't stop taking it, and you still have long-term effectiveness. Studies showing that receptors downregulate in response to an exogenous agent are a sign that the exogenous agent is actually doing what it's supposed to: ie increasing the levels of that neurotransmitter, hormone, whatever

>Interesting that amineptine down-regulates D2 receptors. That
means it must not inhibit the release of dopamine like Ritalin.

It definitely does.

>I think drugs like wellbutrin that do inhibit release of dopamine do
not down-regulate D2

They definitely do, or at least methylphenidate definitely does. Wellbutrin may be a little more complicated due to it's complex actions on multiple receptors.

Re-regulation in different parts of the brain also occurs at different speed. For instance, euphoria from dopaminergics is related to activity in the nucleus accumbens, to which tolerance develops extremely quickly. It is not especially possible to maintain euphoria with any current dopaminergic agent.

OTOH, certain effects of dopaminergics actually develop reverse tolerance, ie the sensitization you mentioned, even as receptors re-regulate. This generally includes most of the "therapeutic" effects of psychostimulants for ADD/ADHD, hence people (most, even) that are able to take the same dose of a stimulant therapeutically for years or more.

[graatch]

>For example, "Chronic treatment with amineptine induces downregulation of dopamine D2, beta- and alpha 2-adrenergic receptors." [http://www.amineptine.com/aminep.htm] What is the consequence of this, subjectively and physiologically?

Probably a two-week or so* "rebound" period after a long course of amineptine is discontinued. OTOH, amineptine should also cause sensitization -- perhaps more powerfully than amphetamine or methylphenidate, since subchronic stress/sleep interference that these agents can cause in the susceptible could in theory interfere with the mechanism of sensitization.

* (in my experience with these drugs, including amineptine)

[theta]

>I think drugs like wellbutrin that do inhibit release of dopamine do
not down-regulate D2

They definitely do, or at least methylphenidate definitely does.  Wellbutrin may be a little more complicated due to it's complex actions on multiple receptors.

Yeah methylpheidate does not inhibit the release of dopamine but
wellbutrin does. Thats why it has abuse potential and wellbutrin
has nearly zero abuse potential. I think wellbutrin does not down-regulated receptors or is similar to SSRI initial down-regulation followed by normalization. The point being many abusable drugs
can down-regulate D2 receptors long term in a fashion that is
known to promote addiction. Though there is a study showing
kids with ADHD that have been treated with stimulants did not
have long term down-regulation of D2 later in life. Suggesting
they would infact less likely to abuse various drugs later in life.

[graatch]

Thats why it has abuse potential and wellbutrin has nearly zero abuse potential.

Well, I would guess that wellbutrin even has less affinity for the reuptake pumps than methylphenidate does, which is actually somewhat preferential for dopamine over norepinephrine (though not as much as amineptine). Hence, yeah, with wellbutrin you tend to have nervousness predominating over the effect that people that want to get high are seeking: euphoria. Another thing is the fairly low dose at which untoward effects might start to occur, ie seizures, so you can't ratchet up too much past therapeutic dose ranges. There are a few reports on erowid with people snorting wellbutrin for euphoria though, heh.

Not to say that norepinephrine plays no role in reinforcement/feelings of pleasure. I mean you would think that amineptine would be the most pleasant/abusable of all dopaminergics, or L-DOPA with carbidopa would be, but in fact they are not.

I think wellbutrin does not down-regulated receptors or is similar to SSRI initial down-regulation followed by normalization.

Heh. SSRIs have some of the worst withdrawal symptoms ever, dude. Ever heard of brain shocks? No one withdrawing from dopaminergics get that. Not to mention the long-term, lasting sexual problems that seem to be cropping up with a number of people who get off of their SSRIs.

As far as the ADD/ADHD drugs go, only methamphetamine has been shown to cause permanent deficits in functioning in humans (at very high doses that induce hyperthermia), and that's not a regulatory mechanism. "Even" the effects of long-term, heavy cocaine use seem to recover in some months.

Suggesting they would infact less likely to abuse various drugs later in life.

This has been confirmed in a few studies.

http://www.additudem...rticle/664.html
http://www.pslgroup.com/dg/11cada.htm

[theta]

There are a few reports on erowid with people snorting wellbutrin for euphoria though, heh.

Someone has a US patent on nasal use of wellbutrin. Too lazy to
look it up for you but basically wellbutrin is poorly orally absorbed so if you use it in the form of a nasal spray or gel you can use a much smaller dose and possibly get a higher percentage of the dopamine re-uptake action since the noradrenaline re-uptake effects are from secondary metabolites. I dissolved some wellbutrin tablets in some
saline nasal spray and adjusted the pH up to a comfortable range as the patent suggested. I was all confident it would solve my ADHD
problems but was not impressed with it. Plus nasal spray is still an
abomination. The gel might be better.

[flatline]

>Interesting that amineptine down-regulates D2 receptors. That
means it must not inhibit the release of dopamine like Ritalin.
>>It definitely does.

This study seems to support what you say:
http://amineptine.com/dopamine.html
"These data indicate that amineptine inhibits DA uptake and is virtually devoid of DA releasing effects."


>Not to say that norepinephrine plays no role in reinforcement/feelings of pleasure.

Strattera, an SNRI, had the nice side effect of instilling a comfortable level of euphoria for a period of days to weeks.


>I was all confident it would solve my ADHD problems

Kudos for trying. You may find the following article interesting: http://www.antiaging...extract/add.htm

[flatline]

additionally, I received the following helpful reply from an administrator at the abolitionist-society.com forum:


Subjectively, down-regulation is described as causing a blunting effect - attenuating the percieved intensity of a particular receptor group - you're best bet is to look on forums like dr. bob for a good variety of subjective reports.

the effect is reversible over time.

You may experience a desensitization of a specific receptor-type via downregulation, but tolerance in terms of efficacy may still be achieved with down-regulation if the stimulation levels are continuously above theraupeutic threshold, it's hard to show a direct correlation as there are so many mechanisms at play. Drugs are still pretty crude mechanisms.

[theta]

additionally, I received the following helpful reply from an administrator at the abolitionist-society.com forum:


Subjectively, down-regulation is described as causing a blunting effect - attenuating the percieved intensity of a particular receptor group - you're best bet is to look on forums like dr. bob for a good variety of subjective reports.

Yeah I saw a title of a study that said a D2 agonist was tested for
social anxiety disorder(SAD). There is some reduce D2 acitivity asociated with SAD. Anyway I could not find the results of that study
for free but some people on Dr-Bob's forum tested simlar drugs and came to the conculsion the drugs works short term (I think a month or so) for SAD but then stop. Thats not surprising because I think
such drugs loose effectiviness with parkinson rapidly and the dose people take can build to 100 mg for a drug like bromocriptine which is a potent drug at even 1 mg.