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Bupropion - Toxicity and similarities to amphet.


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#1 dreamwolf

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Posted 08 October 2007 - 08:43 PM


Hello,

I was wondering given the structure of bupropion if there exists any potential for neurotoxicity in the more conventional sense - ie destruction of axons or neuronal cell bodies. (Metabolites of Bupropion) Also the consequences of this known metabolite - meta-chlorobenzoic acid (see Wellbutrin Pharmacology)

Also I found this interesting - if marginally off-topic:
Link

The effect of BChE on bupropion, a dopamine uptake inhibitor, was surprising. Although bupropion does not contain an ester, the enzyme was an effective bupropion antagonist (data not shown). It is possible that a bupropion metabolite is an ester; this would explain the finding that meta-chlorobenzoic acid is produced as a major bupropion metabolite (Schroeder, 1983). It is also possible that bupropion interacts directly with the enzyme; bupropion was found to inhibit butyrylthiocholine hydrolysis in vitro (data not shown). Taken together with published data on the specificity of the enzyme effect for cocaine relative to phenylephrine (Mattes et al., 1997), the data argue that BChE is responsible for cocaine antagonist effects, even in an impure enzyme preparation.


Are there any studies that have examined the effects of chronic bupropion use on animals in regards or that could be held in regards to neurotoxicity?

Thank you!

#2 theta

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Posted 08 October 2007 - 10:00 PM

Neurotoxicity from methamphetamine in various studies was reduced
with vitamin E, melatonin, coQ10, selenium, carnitine , ALC, deprenyl
, and n-acetyl-cysteine. Mentioned also was lipioc acid, resvertrol and
creatine.

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#3 dreamwolf

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Posted 09 October 2007 - 06:24 PM

Also; since bupropion is the chemical analog of Diethylpropion and such has been demonstrated to have neurotoxic effect (see Neurotoxicity of diethypropion)

Would this have any bearing on determining if bupropion is nerotoxic?

#4 theta

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Posted 09 October 2007 - 09:40 PM

I guess its a matter of it's effective antidepressant dosing verses
high doses that would be needed to get a stimulant response. I assume its nearly impossible to get a stimulant action from
Bupropion from oral use. Its poorly absorbed orally and likely alot
of its action is from its metabolites that are potent noradrenaline
re-uptake inhibitors. Abused by snorting it would be highly bio-available and a large dose would have a much greater
dopamine re-uptake inhibiting action initially and perhaps in high
enough doses it might stimulate the release of dopamine. Seems if that is all true you would beable to find studies on neurotoxocity of
bupropion but only with insane dosing.

This study suggested Bupropion might prevent some of the neurotoxic effects of methamphetamine.

1: Brain Res. 1990 Apr 16;513(2):274-9.
Links
Dopamine uptake inhibitors block long-term neurotoxic effects of methamphetamine upon dopaminergic neurons.
Marek GJ, Vosmer G, Seiden LS.

Department of Pharmacological and Physiological Sciences, University of Chicago, IL 60637.

A single large dose (100 mg/kg, s.c.) of methamphetamine (MA) is known to exert neurotoxic effects on dopaminergic neurons. The potency at which a series of dopamine (DA) uptake inhibitors blocked MA-induced neostriatal depletions (amfonelic acid (AFA) much greater than mazindol (MAZ) greater than or equal to bupropion (BUP) greater than benztropine (BENZ)) was similar to their potency at blocking 6-hydroxydopamine (6-OHDA) neurotoxicity in rats. Amfonelic acid was able to block long-term neostriatal DA depletions when given 8 h, but not 16 h, after a single large MA dose. These results suggest that an intact and functional DA uptake site is necessary for the development of MA-induced long-term DA depletions.

PMID: 2140952 [PubMed - indexed for MEDLINE]



#5 FunkOdyssey

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Posted 09 October 2007 - 10:39 PM

In addition to protecting against amphetamine neurotoxicity it seems to have anti-inflammatory properties as well:

A new chapter opens in anti-inflammatory treatments:The antidepressant bupropion lowers production of tumor necrosis factor-alpha and interferon-gamma in mice

D. Brustolima, 1, R. Ribeiro-dos-Santosa, 1, R.E. Kastc, and M.B.P. Soaresa,
Centro de Pesquisas Gonçalo Moniz, FIOCRUZ. Rua Waldemar Falcão, 121- Candeal, Salvador, BA, Brazil, 40296-750
Department of Physical Medicine and Rehabilitation, New Jersey School of Medicine and Dentistry, USA
Department of Psychiatry, University of Vermont, USA

Received 20 December 2005;  accepted 21 December 2005.  Available online 25 January 2006.

Abstract

In a wide range of human diseases of inflammatory nature like Crohn's disease, pathology is mediated in part by pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF) or interferon-gamma. We show here that a commonly used generic antidepressant bupropion, in wide use worldwide to treat depression in humans for a decade now, profoundly lowers levels of TNF, interferon-gamma, and interleukin-1 beta in vivo, in a mouse lipopolysaccharide (LPS) induced inflammation model. Mice challenged with an otherwise lethal dose of LPS were protected by bupropion and levels of the anti-inflammatory cytokine interleukin-10 were increased. Previous data in rodents and humans indicate antidepressant effects of bupropion are mediated by its weak reuptake inhibition of norepinephrine and dopamine. Concordant with this, TNF suppression by bupropion in our mouse LPS model was largely abrogated by beta-adrenergic or dopamine D1 receptor antagonists but not by a D2 antagonist. TNF synthesis is controlled by an inverse relationship with intracellular cyclic adenosine monophosphate (cAMP) and stimulation of either beta-adrenoreceptors or D1 dopaminergic receptors result in increased cAMP but stimulation of D2 receptors lowers cAMP. We conclude that bupropion may suppress TNF synthesis by mediating increased signaling at beta-adrenoreceptors and D1 receptors, resulting in increased cAMP that inhibits TNF synthesis. Bupropion is well tolerated also in non-psychiatric populations and has less risk with long term use than current anti-inflammatory, immunosuppressive or TNF suppressive treatments such as prednisone, azathioprine, infliximab, or methotrexate. New anti-inflammatory treatments are needed. We believe a new chapter in antiinflammatory, TNF lowering treatment of disease has been opened. Bupropion's use for this in humans should be explored.



#6 dreamwolf

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Posted 17 October 2007 - 05:37 PM

That bupropion shows neuroprotective effects in regards the meth-induced dopaminergenic neurotoxicity is good. However the question that still arises in my mind is one of toxicity towards serotonin axons/cell bodies. On this subject I have found little material to eliminate the concern.

Possibly I should rephrase the question. How many present have had positive experiences with chronic bupropion/wellbutrin/zyban usage? ie no reduction or an enhancement in cognitive capabilities?

#7 FunkOdyssey

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Posted 18 October 2007 - 01:56 PM

However the question that still arises in my mind is one of toxicity towards serotonin axons/cell bodies. On this subject I have found little material to eliminate the concern.

What material have you found that raised concern in the first place? Bupropion increases the firing rate of serotonin neurons indirectly through enhancement of NE release, but I haven't seen any mention of this having negative implications.

How many present have had positive experiences with chronic bupropion/wellbutrin/zyban usage? ie no reduction or an enhancement in cognitive capabilities?

*raises hand*

#8 graatch

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Posted 18 October 2007 - 04:02 PM

>Seems if that is all true you would beable to find studies on neurotoxocity of
bupropion but only with insane dosing.

Chronic norepinephrine release strikes me as something that's going to be a lot more potentially toxic than dopaminergic activity, not chiming in specifically on the bupropion issue yet.

What needs to be discovered is the mechanism behind seizure threshold activity. It was smart to bring up diethylpropion -- I'll try looking into research on this soon.

>protecting against amphetamine neurotoxicity

Yea, reuptake inhibitors protect against amphetamine neurotoxicity in general. It'd be a wise decision for anyone using high doses of amphetamine (or MDMA) for whatever great reason to try trading out a little bit for a small amount of ritalin for instance.

#9 graatch

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Posted 18 October 2007 - 04:04 PM

Depression OTOH is obviously, demonstrably and powerfully neurotoxic.
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#10 dreamwolf

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Posted 18 October 2007 - 04:23 PM

So you have had a good experience on Bupropion - no negative effects?

Well....My experience with Bupropion started in May. The first time I took the 150mg SR dose of budeprion (generic of wellbutrin) I noticed I could not sleep the following night - not that I tried that hard. Throughout the month I seemed to notice a further reduction in my ability to remember things as well as extreme difficulty following basic conversations and remembering them for more than a couple of minutes. Needless to say I found all of this extremely concerning - especially given that I work and pride myself as a computer technician. When starting to taper and then withdraw from the wellbutrin my symptoms became worse, panic attacks and extreme anxiety and inability to enjoy sleep/sleep until noon or whenever were added, and have taken several months to show any degree of improvement.

Now there are other commingling circumstances in this as well such as separation from my wife and kids in April, having a girlfriend that moreso initially had a tendency to over analyze things and always see the negative, loss of a primary friend, and criticism from the family that I became involved with this woman before I was divorced.

The links have been posted previously:


Bupropion Private Study

Also note this excerpt from the study:

3.      Bupropion is chemically unstable, in aqueous solutions and in the pill form - either during manufacture or post manufacture. On the basis of blood tests presented herein and from the literature, it is unstable in the human body as well.  In the formulation, bupropion will undergo N-dealkylation to form two conjugated materials that will rapidly react in vitro to form 2-Amino-1-(3-chloro-phenyl)-propan-1-ol (hydroxybupropamine or HBA - not to be confused with hydroxybupropion, which is a known metabolite of bupropion.)  HBA fits into the category of indirect-acting adrenergic agonist and is most similar in structure to meta-chloroamphetamine (MCA) - a potent neurotoxin that has multiple effects on the brain and the body.  It is probable, based upon literature studies that have determined degradation of bupropion in the blood and upon literature studies showing false positive amphetamine results when bupropion is taken, these two degradation products will form HBA in vivo as well.  In aqueous solutions and in a blood simulating mixed solvent system, the resultant products of this instability are erythrohydrobupropion (EB), threohydrobupropion (TB), 2-Amino-1-(3-chloro-phenyl)-2-propen-1-one, HBA and meta-chlorobenzoic acid (MCBA). All five of the degradation products exhibit pharmacological activity.


In regards to the probable - please note the blood samples that were taken from several volunteers later on in the paper that showed the presence of HBA in the blood.

Note the references at the bottom - specifically 112-116 that relate to the metabolism of a similar drug, Diethylpropion (Tenuate) and it's transition to HBA.

I have found studies that cite MDMA as a cause for panic attacks several months down the road from the first dose; thusly reinforcing the hypothesis that bupropion's metabolites are nerotoxic to serotonin axons.

Admittedly - Similar in structure to chloroamphetamines or chlorophentermine does not necessarily equate to similar in function. Thus the 'hand-waving' disclaimer at the end of the study. It has however been enough to cause great concern on my part until proven otherwise that bupropion's metabolites may have caused irreparable damage to my brain.

So....I need to know either more positive experiences taking wellbutrin (ideally the generic from Teva - and bonus points if you stored the drug in a hot cabinet/house exceeding 77 F) or proof that the metabolite of wellbutrin - 2-Amino-1-(3-chloro-phenyl)-propan-1-ol (hydroxybupropamine or HBA) - is either non-existent or not neurotoxic or recovering my normal functioning.

In the meantime every day pretty much seems like hell to me as I am left feeling like I am but a shell of my previous self.

If not for having the support of my girlfriend during this time - I'd probably end up offing myself - which is a 180 degree reversal from my normal attitude of wanting to live forever.

Any help in terminating this concern with 'extreme prejudice' is appreciated!

PS - Replies that just state 'Not likely' or similar without stating a line of reasoning or relation of personal experience with the drug will not be helpful.

Edited by dreamwolf, 18 October 2007 - 04:39 PM.


#11 graatch

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Posted 18 October 2007 - 08:50 PM

>The first time I took the 150mg SR dose of budeprion (generic of wellbutrin) I noticed I could not sleep the following night - not that I tried that hard. Throughout the month I seemed to notice a further reduction in my ability to remember things as well as extreme difficulty following basic conversations and remembering them for more than a couple of minutes.

This experience doesn't need to (and probably doesn't, since we have another obvious mechanism) indicate neurotoxicity. Bupropion is functionally anticholinergic at nicotinic receptors.

>When starting to taper and then withdraw from the wellbutrin my symptoms became worse, panic attacks and extreme anxiety and inability to enjoy sleep/sleep until noon or whenever were added, and have taken several months to show any degree of improvement.

Also doesn't need to reflect toxicity, just re-regulatory mechanisms. Most things have a withdrawal syndrome, and bupropion and its metabolites have a long-ass half-life, which will extend the duration of symptoms. Also, if you got depressed, this will potentiate said effects.

As to your metabolites, it's a pretty interesting issue that I'll try looking into. I hope I can help you out.

#12 graatch

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Posted 19 October 2007 - 03:38 AM

The thing that strikes me as the most underhandedly possibly toxic about bupropion? The half-life. You're never going to sleep without adrenaline pumping.

This effect probably improves with time.

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#13 dreamwolf

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Posted 19 October 2007 - 05:53 PM

I eagerly await your conclusion on the subject. Since I last posted I have spoken with someone whom has had a good experience with taking the generic bupropion and has since been on three seperate courses for smoking/chewing cessation. His report has led me to cast doubt upon my hypothesis - but has not completely eliminated it. Also he is a very high functioning individual with an excellent memory.

I still would like to press my doc (a neuropschyc) to do an mri and a pet scan looking for sert- or 5ht receptor binding levels to put an end to my worries. He doesn't however think these scans would do any good in showing any potential damage? Why would the pet scan be used in studies looking for damage in humans relating to mdma then? A high cost for piece of mind to be sure - and I don't think I'll ever be taking wellbutrin again given what I have learned about the substance.




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