31 replies to this topic

[k10]

Has anyone tried for this for ADD? Apparently it should be superior to selegiline since it doesn't break down into the neurotoxic amphetamine metabolites, and is also much more potent.

I got a prescription from my psychiatrist and will be trying it sometime this week. It was 100% covered by insurance! I've only ever heard one case report on the internet of it being used for ADD and the report was quite positive so I'm quite excited to give it a try. I have a feeling that it should give a smooth boost in attention and motivation without any sort of over-stimulation or side effects. It should also provide neuroprotection.

[chrono]

Will be very interested to hear how this works out for you. My next order is going to be some deprenyl...I'm hoping that it will provide some of the motivational (and maybe socially anxiolytic) component that adderall gives me. But I'm trying to keep my expectations low; a lot of people have reacted poorly (irritability), and most seem to notice only a subtle improvement.

Rasalgaline would definitely be preferable, due to the metabolite issue.

[FunkOdyssey]

Over at M&M there's alot of discussion about how deprenyl seems to induce symptoms of CFS or HPA axis dysfunction over time in many users, nearly half by some estimates. Its possible the rasagiline would cause the same problems since they are so similar.

[Ephilation]

As Chrono said, please do continue to post and let us know your results. I know it'll be some time before you can tell what the medicine is doing (say, 6 weeks or so), but I too would be interested in trialling this medication. Expensive, but it might be worth it.

[medievil]

How would the metabolites be problematic? Its my understanding that they arent active in those low doses.

[chrono]

How would the metabolites be problematic? Its my understanding that they arent active in those low doses.

Actually, I think you're right; it wouldn't be problematic for the reason I thought.

This paper shows that the levels of l-methamphetamine are pretty low, so they're probably not active to a very appreciable amount at the dosages we're talking about.

l-methamphetamine pharmacokinetics and pharmacodynamics for assessment of in vivo deprenyl-derived l-methamphetamine. [free full text]
Melega WP, Cho AK, Schmitz D, Kuczenski R, Segal DS.

Brain and plasma levels of deprenyl andl-MeAmp were measured after deprenyl (10 mg/kg s.c.) from 10 to 60 min in conscious rats.
..
Dopamine response-area under curve versus dose plots were generated and used to show that an administered dose of 4 mg/kg l-MeAmp would be necessary to effect a dopamine response-area under curve comparable to that observed after the deprenyl dose. However, the present pharmacokinetic results indicated that l-MeAmp brain levels after deprenyl corresponded to those that would be obtained from 0.4 mg/kgl-MeAmp (i.e., one tenth of the required dose). Collectively, these results suggest that the acute increases in extracellular dopamine observed after deprenyl are not due uniquely to metabolically generated l-MeAmp but also to other actions of deprenyl at the dopamine terminal.
...
Peak caudate-putamen MeAmp levels at 30 min (3 nmol/g) were approximately 20% of those of peak deprenyl (15 nmol/g).
...
However, throughout 50 min post-l-MeAmp, brain levels of l-Amp and p-OH-l-Amp did not exceed 12% and 0.25% of those of l-MeAmp, respectively. Accordingly, we concluded that l-MeAmp was the primary active metabolite during the initial 50 min after deprenyl administration. Although another deprenyl metabolite, desmethyldeprenyl, was not measured, other studies had shown that its levels remained less than 5% those of deprenyl.

I was thinking more along the lines of methamphetamine neurotoxicity. But it seems this isn't an issue; for example, this study found meth neurotoxicity (in rats) only after repeated overlapping sc injections at 4mg/kg, which is 10x the amount of meth found after a 10mg/kg sc injection of deprenyl in rats. Which corresponds to about a 1.6mg/kg human dosage? (i.e. incredibly large).

And aside from all that, this abstract seems to think it's ok.

Are metabolites of l-deprenyl (selegiline) useful or harmful? Indications from preclinical research.
Yasar S, Goldberg JP, Goldberg SR.
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Medical School,

A frequent topic of controversy has been whether metabolism of l-deprenyl (selegiline) to active metabolites is a detriment to clinical use. This paper reviews possible roles of the metabolites of l-deprenyl in producing unwanted adverse side effects or in augmenting or mediating its clinically useful actions. Levels of l-amphetamine and l-methamphetamine likely to be reached, even with excessive intake of l-deprenyl, would be unlikely to produce neurotoxicity and there is no preclinical or clinical evidence of abuse liability of l-deprenyl. In contrast, there is evidence that l-amphetamine and l-methamphetamine have some qualitatively different actions than their d-isomer counterparts on EEG and cognitive functioning which might result in beneficial clinical effects and complement beneficial clinical actions of l-deprenyl itself.

PMID: 8988462 [PubMed - indexed for MEDLINE]

Given the choice, I still say it's preferable not to have methamphetamine floating around in your brain, but the practical danger is probably close to zero.

[medievil]

How would the metabolites be problematic? Its my understanding that they arent active in those low doses.

Actually, I think you're right; it wouldn't be problematic for the reason I thought.

This paper shows that the levels of l-methamphetamine are pretty low, so they're probably not active to a very appreciable amount at the dosages we're talking about.

l-methamphetamine pharmacokinetics and pharmacodynamics for assessment of in vivo deprenyl-derived l-methamphetamine. [free full text]
Melega WP, Cho AK, Schmitz D, Kuczenski R, Segal DS.

Brain and plasma levels of deprenyl andl-MeAmp were measured after deprenyl (10 mg/kg s.c.) from 10 to 60 min in conscious rats.
..
Dopamine response-area under curve versus dose plots were generated and used to show that an administered dose of 4 mg/kg l-MeAmp would be necessary to effect a dopamine response-area under curve comparable to that observed after the deprenyl dose. However, the present pharmacokinetic results indicated that l-MeAmp brain levels after deprenyl corresponded to those that would be obtained from 0.4 mg/kgl-MeAmp (i.e., one tenth of the required dose). Collectively, these results suggest that the acute increases in extracellular dopamine observed after deprenyl are not due uniquely to metabolically generated l-MeAmp but also to other actions of deprenyl at the dopamine terminal.
...
Peak caudate-putamen MeAmp levels at 30 min (3 nmol/g) were approximately 20% of those of peak deprenyl (15 nmol/g).
...
However, throughout 50 min post-l-MeAmp, brain levels of l-Amp and p-OH-l-Amp did not exceed 12% and 0.25% of those of l-MeAmp, respectively. Accordingly, we concluded that l-MeAmp was the primary active metabolite during the initial 50 min after deprenyl administration. Although another deprenyl metabolite, desmethyldeprenyl, was not measured, other studies had shown that its levels remained less than 5% those of deprenyl.

I was thinking more along the lines of methamphetamine neurotoxicity. But it seems this isn't an issue; for example, this study found meth neurotoxicity (in rats) only after repeated overlapping sc injections at 4mg/kg, which is 10x the amount of meth found after a 10mg/kg sc injection of deprenyl in rats. Which corresponds to about a 1.6mg/kg human dosage? (i.e. incredibly large).

And aside from all that, this abstract seems to think it's ok.

Are metabolites of l-deprenyl (selegiline) useful or harmful? Indications from preclinical research.
Yasar S, Goldberg JP, Goldberg SR.
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Medical School,

A frequent topic of controversy has been whether metabolism of l-deprenyl (selegiline) to active metabolites is a detriment to clinical use. This paper reviews possible roles of the metabolites of l-deprenyl in producing unwanted adverse side effects or in augmenting or mediating its clinically useful actions. Levels of l-amphetamine and l-methamphetamine likely to be reached, even with excessive intake of l-deprenyl, would be unlikely to produce neurotoxicity and there is no preclinical or clinical evidence of abuse liability of l-deprenyl. In contrast, there is evidence that l-amphetamine and l-methamphetamine have some qualitatively different actions than their d-isomer counterparts on EEG and cognitive functioning which might result in beneficial clinical effects and complement beneficial clinical actions of l-deprenyl itself.

PMID: 8988462 [PubMed - indexed for MEDLINE]

Given the choice, I still say it's preferable not to have methamphetamine floating around in your brain, but the practical danger is probably close to zero.

But would that be the case tough?

Low doses of methamphetamine can actually induce neuroprotective changes rendering protection against further high doses of methamphetamine as seen in this study. Maybe the metabolites actually contribute to deprenyl's neuroprotective effect?

That said i have chosen to avoid deprenyl since it can actually have a negative in higher doses and increase mortality, how do we know the optimal dose for humans? Besides that am i not sure wheter its actually a good idea to start using it at a young age.

Edited by medievil, 23 June 2010 - 02:05 PM.

[chrono]

I think the neuroprotective effects of low-dose methamphetamine might be limited to the case of preconditioning for subsequent meth doses (or perhaps other drugs which might deplete dopamine). A few other papers I came across suggest that rasalgaline is equally neuroprotective in several models.

Contrasting neuroprotective and neurotoxic actions of respective metabolites of anti-Parkinson drugs rasagiline and selegiline.
Bar Am O, Amit T, Youdim MB.

The anti-Parkinson selective irreversible monoamine oxidase B inhibitor drugs, rasagiline and selegiline, have been shown to possess neuroprotective activities in cell culture and in vivo models. While rasagiline is metabolized to its major metabolite aminoindan, selegiline gives rise to L-methamphetamine. Cultured PC-12 cells in absence of serum and nerve growth factor (NGF) die by an apoptotic process. Pretreatment of PC12 cells in absence of serum and NGF for 24 h with either rasagiline (1 microM) or selegiline (1 microM) is neuroprotective and anti-apoptotic as determined by ELISA and MTT tests. However, while aminoindan (1 microM), the major metabolite of rasagiline does not interfere with the neuroprotective activities of rasagiline or selegiline in PC-12 cells deprived of serum and NGF, the major metabolite of selegiline, L-methamphetamine (1 microM), inhibits them. In contrast to L-methamphetamine, aminoindan is itself is neuroprotective in this system. Recently it has been demonstrated that rasagiline directly activates PKC-MAP kinase pathway by a concentration and time dependent phosphorylation of p42 and p44 MAP kinase. In the present studies the neuroprotective activity of rasagiline is blocked by ERK inhibitor, PD98059 (20 microM), suggesting the involvement of PKC-MAP kinase pathway in the neuroprotection. These findings may have implication for the possible disease modifying action of rasagiline in treatment of Parkinson's disease.

PMID: 14732458 [PubMed - indexed for MEDLINE]

Monoamine oxidase-inhibition and MPTP-induced neurotoxicity in the non-human primate: comparison of rasagiline (TVP 1012) with selegiline.
Kupsch A, Sautter J, Götz ME, Breithaupt W, Schwarz J, Youdim MB, Riederer P, Gerlach M, Oertel WH.

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to induce parkinsonism in man and non-human primates. Monoamine-oxidase B (MAO-B) has been reported to be implicated in both MPTP-induced parkinsonism and Parkinson's disease, since selegiline (L-deprenyl), an irreversible MAO-B inhibitor, prevents MPTP-induced neurotoxicity in numerous species including mice, goldfish and drosophyla. However, one disadvantage of this substance relates to its metabolism to (-)-methamphetamine and (-)-amphetamine. Rasagiline (R-(+)-N-propyl-1-aminoindane) is a novel irrevesible MAO-B-inhibitor, which is not metabolized to metamphetamine and/or amphetamine. The present study compared the effects of high doses of selegiline and rasagiline (10 mg/kg body weight s.c.) on MPTP-induced dopaminergic neurotoxicity in a non-human primate (Callithrix jacchus) model of PD. Groups of four monkeys were assigned to the following six experimental groups: Group I: Saline, Group II: Selegiline/Saline, Group III: Rasagiline/Saline, Group IV: MPTP/Saline, Group V: Rasagiline/MPTP, Group VI: Selegiline/MPTP. Daily treatment with MAO-B-inhibitors (either rasagiline or selegiline, 10 mg/kg body weight s.c.) was initiated four days prior to MPTP-exposure (MPTP-HCl, 2 mg/kg body weight subcutaneously, separated by an interval of 24 hours for a total of four days) and was continued until the end of the experiment, i.e. 7 days after the cessation of the MPTP-injections, when animals were sacrificed. MPTP-treatment caused distinct behavioural, histological, and biochemical alterations: 1. significant reduction of motor activity assessed by clinical rating and by computerized locomotor activity measurements; 2. substantial loss (approx. 40%) of dopaminergic (tyrosine-hydroxylase-positive) cells in the substantia nigra, pars compacta; and 3. putaminal dopamine depletion of 98% and its metabolites DOPAC (88%) and HVA (96%). Treatment with either rasagiline or selegiline markedly attenuated the neurotoxic effects of MPTP at the behavioural, histological, and at the biochemical levels. There were no significant differences between rasagiline/MPTP and selegiline/MPTP-treated animals in respect to signs of motor impairment, the number of dopaminergic cells in the substantia nigra, and striatal dopamine levels. As expected, both inhibitors decreased the metabolism of dopamine, leading to reduced levels of HVA and DOPAC (by >95% and 45% respectively). In conclusion, rasagiline and selegiline at the dosages employed equally protect against MPTP-toxicity in the common marmoset, suggesting that selegiline-derived metabolites are not important for the neuroprotective effects of high dose selegiline in the non-human MPTP-primate model in the experimental design employed. However, unexpectedly, high dose treatment with both MAO-inhibitors caused a decrease of the cell sizes of nigral tyrosine hydroxylase positive neurons. It remains to be determined, if this histological observation represents potential adverse effects of high dose treatment with monoamine oxidase inhibitors.

PMID: 11716151 [PubMed - indexed for MEDLINE]

Mechanism of neuroprotective action of the anti-Parkinson drug rasagiline and its derivatives.
Mandel S, Weinreb O, Amit T, Youdim MB.

The mitochondria are directly involved in cell survival and death. Drugs that protect mitochondria viability and prevent apoptotic cascade mechanisms involved in mitochondrial permeability transition pore (MPTp) will be cytoprotective. Rasagiline (N-propargyl-1R-aminoindan) is a novel, highly potent irreversible monoamine oxidase (MAO) B inhibitor, anti-Parkinson drug. Unlike selegiline, rasagiline is not derived from amphetamine, is not metabolized to neurotoxic l-methamphetamine derivative, nor does it have sympathomimetic activity. Rasagiline is effective as monotherapy or adjunct to L-dopa for patients with early and late Parkinson's disease (PD), and adverse events do not occur with greater frequency in subjects receiving rasagiline than those on placebo. Controlled studies indicate that it might have a disease-modifying effect in PD that may be related to neuroprotection. Its S-isomer, TVP1022, is a relatively inactive MAO inhibitor. However, both drugs have similar neuroprotective activities in neuronal cell cultures in response to various neurotoxins and in vivo (global ischemia, neurotrauma, head injury, anoxia, etc.), indicating that MAO inhibition is not a pre-requisite for neuroprotection. Structure activity studies have shown that the neuroprotective activity is associated with the propargyl moiety of rasagiline which protects mitochondrial viability and MPTp by activating Bcl-2 and protein kinase C (PKC), and down regulating pro-apoptotic FAS and Bax. Rasagiline and its derivatives also process amyloid precursor protein (APP) to the neuroprotective-neurotrophic soluble APP alpha (sAPPalpha) by PKC and MAP kinase-dependent activation of alpha-secretase. The neuroprotective activity of propargylamine has led us to develop novel bifunctional neuroprotective iron-chelating MAO-inhibiting drugs possessing propargyl moiety for the treatment of other neurodegenerative diseases.

PMID: 15850677 [PubMed - indexed for MEDLINE]

I'm going to give deprenyl a try in the very near future. It seems like one of the only practical options for sustained improvement along the SA/motivation dopaminergic axis. Except perhaps some of the selective dopamine agonists you're looking at, but those seem like more of a long-shot to me in terms of efficacy, with at least as much chance of adverse effects. And the activity-dependent catecholamine activity enhancement (CAE) mechanism seems very elegant to me.

As far as I remember, the increased mortality was shown in one study on PD back in the 90s, which included use of L-DOPA, allowed patients to be switched between DPR/DPR+DOPA groups halfway through without correcting for this in the analysis, and one analysis I read raised the possibility of a bad batch of deprenyl to explain the atypical finding. In any event, I won't be going for any kind of high dose, but will be staying around 5mg or so to maintain MAOI-B selectivity.

The age issue is mentioned a lot on these boards, but I was unable to find any explanation as to why it might be harmful for twentysomethings, let alone any evidence. Four of the six ADHD trials on pubmed involve children, and all of them suggest some degree of efficacy.

Though I do agree, it's a medication to be approached cautiously. If it's anything like effective, I'll probably switch to BPAP once that becomes economically feasible.

Not trying to change your mind, or anything Indeed, I'm watching your various approaches with keen interest.

[aLurker]

Over at M&M there's alot of discussion about how deprenyl seems to induce symptoms of CFS or HPA axis dysfunction over time in many users, nearly half by some estimates. Its possible the rasagiline would cause the same problems since they are so similar.

Could you please provide a link to this discussion. I'd search for it myself but I have no idea what you mean by M&M.

[aLurker]

Selegiline (L-Deprenyl) seems like a tempting prospect in many ways (cheap, many studies on it, helps ADHD, massive increase in lifespan in rats). I might start a new thread to ask specifically if this has helped anyone's motivation. Motivation/drive is probably the only thing that I really need right now, I feel awesome otherwise so the question is if it is worth risking the possible side-effects, perhaps try it out and stop if I get any sides at all. The prospect of side-effects after longer use which FunkOdyssey hints at is the real scare though. Thoughts on taking 1-5 mg for motivation vs. side-effects?

Regarding Deprenyl, here is what a few minutes of looking at wiki told me (not the best of sources I know, so feel free to look it up elsewhere): the deprenyl you guys are talking about is L-Deprenyl which partly metabolises into L-amphetamine and L-methamphetamine. These are much weaker and seem to have way fewer side-effects than D-amphetamine and D-methamphetamine. A prescription and tests distinguishing L from D would in all likelihood clear you in a drug testing situation.

To stay somewhat on topic; Rasagiline seems to work similarly to Deprenyl but without partly metabolising into any amphetamines at all, the biggest concerns for me are the lack of studies so far and the price. It seems very promising on paper so the best of luck and keep us posted!

[k10]

And another great thing about Rasagiline is that not only is it neuroprotective in and of itself, the metabolites of rasagiline are also neuroprotective!

[chrono]

Could you please provide a link to this discussion. I'd search for it myself but I have no idea what you mean by M&M.

Mind & Muscle forums. Lots of the same things under discussion, but with more of a slant toward body modification.

I might start a new thread to ask specifically if this has helped anyone's motivation.

Thoughts on taking 1-5 mg for motivation vs. side-effects?

Maybe do a little searching with google; just add site:imminst.org to the search. DPR and motivation has been mentioned a couple of times here, and there's lots of discussion about side effects at those dosages. Probably useful to search M&M too.

[medievil]

The issue with deprenyl is imo the U dose response curve and its ability to actually cause damage in high doses. Take a look at those studies:

1. Gallagher, I. M., Clow, A., and Glover, V. (1998). Long-term administration of (-)-deprenyl increases mortality in male Wistar rats. J Neural Transm Suppl 52, 315-20.[Abstract]
2. Ann N Y Acad Sci. 2006 May;1067:375-82. The necessity of having a proper dose of (-)deprenyl (D) to prolong the life spans of rats explains discrepancies among different studies in the past.[Abstract]

While its been studies in childeren this doesnt mean that it wont cause long term adverse effects, properties that only show up in the long run, properties i as a life extensionist am concerned about.

The reason i'm concerned about taking deprenyl on a early age is because i remember reading about a LDOPA study were it increased the lifespan of those rats except in the young ones, while LDOPA is completely differend this does show that age can have a big influence on the end outcome. That said i will probably start supplementing resveratrol pretty soon where this can also be an issue with.

Edited by medievil, 25 June 2010 - 10:38 AM.

[aLurker]

Very interesting post there medievil. Here is an interview with Joeseph Knoll the discoverer of Deprenyl:

We know now that 0.01 milligrams per kilogram of deprenyl is sufficient to exert an enhancer effect. Thus the 0.5 milligrams per kilogram dose was obviously enormously high, and this explains why Kitani and colleagues found no sign of the significant extension in the longest survival which appeared in our studies and in the Milgram et al. study.

So obviously those dosages in the studies you mentioned were WAY too high.

Q: How might healthy people utilize deprenyl for its cognitive enhancing and antiaging benefits?

Dr. Knoll: They should take one milligram of deprenyl daily from sexual maturity until death.

This is far more interesting to me than overdosing; dosed properly, deprenyl prolongs life in mice, in rats, in hamsters, and in dogs. No similar studies of humans that I know of so far though. I have no idea if a dose of 1.25 mg (quarters of 5 mg pills, perhaps step it down and skip days to get to 1 mg per day average) or so would give me any increase in motivation though but I'm REALLY REALLY tempted to try. I've read a lot about Deprenyl on these forums so far and very few people seem to take Deprenyl in low dosages without doing something questionable such as trying to get high with PEA or similar substances.

[chrono]

The issue with deprenyl is imo the U dose response curve and its ability to actually cause damage in high doses. Take a look at those studies:

While its been studies in childeren this doesnt mean that it wont cause long term adverse effects, properties that only show up in the long run, properties i as a life extensionist am concerned about.

Good papers, and I think you make a good point. There were incredibly heated and intricate debates about deprenyl on alt.sci.life-extension back in the mid-90s that I haven't got around to wading through yet. There seems to be some conflicting data, confounding factors, and trouble reproducing results.

The fact that Knoll says 0.5mg/kg is "extremely high" isn't that comforting. The BSA formula for extrapolating rat dosage to humans is to devide by ~6, IIRC. That number is barely larger than what 5mg equals for a 70kg human, and it's desirable to have a good safety margin after that computation. Though that formula may not apply to whatever mechanism is causing an increased mortality in these studies. I hope my calculations are very wrong, because 5mg is on the low end of the therapeutic dosage range.

To be honest, I'm really looking for a short-term solution at the moment, to help me out in fixing some problems with myself and my situation, and DPR seems like a pretty good bet. But I agree that a through analysis of available literature and opinions would be necessary before a therapeutic dose is considered long-term. Various recommendations for 1mg (or less) every day (or less frequently) might be worth considering for the purpose of life extension, though; but again, I haven't reviewed data thoroughly enough to suggest this is a great idea.

(k10, sorry to discuss something on a bit of a tangent, but I think there's a good chance this might apply to rasalgaline to some extent if is shares some mechanisms with DPR. And since every thread here gets flooded with random experiences about whatever is being discussed, I feel like it's somewhat excusable for scientific discourse )

[aLurker]

The fact that Knoll says 0.5mg/kg is "extremely high" isn't that comforting. The BSA formula for extrapolating rat dosage to humans is to devide by ~6, IIRC. That number is barely larger than what 5mg equals for a 70kg human, and it's desirable to have a good safety margin after that computation. Though that formula may not apply to whatever mechanism is causing an increased mortality in these studies. I hope my calculations are very wrong, because 5mg is on the low end of the therapeutic dosage range.

Very interesting. A dose of 0.5 was too high but 0.25 mg/kg seemed to work just fine for rats. According to your estimates, I as a 70 kg human in his twenties should then make sure to stay under roughly 2.5 mg for longevity. That is, whole 5 mg pills could potentially hurt my lifespan but 1-2.5 mg should actually be helpful.

Worth mentioning is that the effects of this drug (and Rasagiline too I suppose) are cumulative and a lesser dose might be needed long-term. That is if I start out with a higher dose I might be able to retain the therapeutic effects at a lower dose, or is this wishful thinking from my part? My thought is that I might initially be able to step up the dosage gradually until I get the desired effects and then step it down to a safe level (<=2.5 mg) when I get results and hopefully still retain them.

[chrono]

Worth mentioning is that the effects of this drug (and Rasagiline too I suppose) are cumulative and a lesser dose might be needed long-term. That is if I start out with a higher dose I might be able to retain the therapeutic effects at a lower dose, or is this wishful thinking from my part?

From what I recall in my forum readings, this idea was based on the irreversibility of the MAOI effect, and that less would be needed once suppression was initially established. I think that in the early literature and much current discussion, there's a tendency to attribute most of DPR's effects to MAO inhibition. I'm not sure how much is actually due to the CAE effect, as there have been comparably few studies on effectively non-MAOI CAEs like BPAP. But they do possess definite mood-altering effects. Of particular interest to you might be Neurochem Res. 2003 Aug;28(8):1275-97, which examines the CAE effect on innate and acquired drives, as these models probably intersect with the kind of motivation we're discussing.

[aLurker]

I did some math according to Dose translation from animal to human studies revisited

Here is how you do it: HED(mg/kg) = Animal dose (mg/kg) multiplied by (Animal Km / Human Km)
Where Animal Km is for instance 3 for rats and 37 for an adult human of 60 kg (Table 1 in the pdf).

So 0.5 mg/kg, which was too high for a rat would then be the following for a 60 kg adult:
0.5*(3/37)*60=2.43 mg, which would mean that 2.5 mg of Deprenyl per day is probably too high if taken for longevity!

And 0.25 mg/kg, which seemed to extend life in rats would give us
0.5*(3/37)*60=1.21 mg, which indicates that 1.25 actually seems to be the appropriate dosage for increasing lifespan in humans.

So according to my calculations (which I implore you all to double-check) a dose as low as 2.5 mg per day of Deprenyl might actually be harmful, at least in the long run. ~1-1.25 mg/day seems to be far superior health wise.
Of course one should bear in mind that these are studies on animals and not humans after all.

I haven't found any studies testing whether such a low dose actually has any therapeutic effects in humans (the lowest dosages tested I could find were 5 mg/day, I found one study where they tested 1.25 mg Zydis Selegiline and got results but that one has better bio-availibilty than regular Selegiline it seems so it doesn't really count in my mind). So whether such a low dose as 1.25 mg per day could give statistically significant effects in humans is still up in the air.

[aLurker]

Chrono, from the article you mentioned, Knoll says:

According to the available experimental and clinical data, it is reasonable to expect that daily administration of an enhancer drug [e.g., deprenyl 1 mg or BPAP) 0.1 mg] from sexual maturity until death will improve the quality of life in the latter decades, shift the time of natural death, decrease the precipitation of age-related depression, and reduce the prevalence of Parkinson’s disease and Alzheimer’s disease.

No mention of motivation though and I have no idea what he thinks is the superior alternative between Deprenyl and BPAP though, especially when it comes to motivation. Some article I read somewhere said that Knoll himself takes 1 mg of Deprenyl daily but I'd really want a proper source for that statement.

It was a very technical article though and I suspect that it would take me a lot of time to understand it in any deeper sense. I'll try to read more of it later, although that statement might just be a result of lacking motivation and procrastination.

To actually stay on topic somewhat 1 mg of Rasagiline daily seems to be common dosage (http://www.ncbi.nlm....pubmed/20236308 for instance). Makes you wonder how much more potent Rasagiline is than Deprenyl and whether Deprenyl also would have a therapeutic effect in lower dosages than studied so far. No idea if there are any studies on life extension and Rasagiline either for that matter.

Found a link to Dr. Knoll's book too.

http://books.google....(-)BPAP&f=false

[chrono]

lurker, thanks for that paper. The Km value for rats is 6, not 3 (mouse). So you divide by 6.16 to get the human equivalent mg/kg dose.

[aLurker]

Oh, that error is actually great news for me! I'll edit my previous post (or repost it with the correct numbers). This actually makes me feel much more optimistic about trying Deprenyl since it means I'll have more wiggle room when it comes to dosage. :D

[aLurker]

CORRECTED VERSION of previous post (adjusted for rats, not mice, thank you Chrono), admins feel free to delete the previous post which was of by a factor of two which is not a trivial magnitude

I did some math according to Dose translation from animal to human studies revisited

Here is how you do it: HED(mg/kg) = Animal dose (mg/kg) multiplied by (Animal Km / Human Km)
Where Animal Km is for instance 6 for rats and 37 for an adult human of 60 kg (Table 1 in the pdf).

So 0.5 mg/kg, which was too high for a rat would then be the following for a 60 kg adult:
0.5*(6/37)*60=4.86 mg, which would mean that 5 mg of Deprenyl per day is probably too high if taken for longevity!

And 0.25 mg/kg, which seemed to extend life in rats would give us
0.25*(6/37)*60=2.43 mg, which indicates that 2.5 actually seems to be more appropriate dosage for increasing lifespan in humans.

So according to my calculations (which I implore you all to double-check) a dose as low as 5 mg per day of Deprenyl might actually be harmful, at least in the long run. ~0.1-2.5 mg/day seems to be far superior health wise.
Of course one should bear in mind that these are studies on animals and not humans after all.

I haven't found any studies testing whether such a low dose actually has any therapeutic effects in humans (the lowest dosages tested I could find were 5 mg/day, I found one study where they tested 1.25 mg Zydis Selegiline and got results but that one has better bio-availibilty than regular Selegiline it seems so it doesn't really count in my mind). So whether such a low dose as 2.5 mg per day could give statistically significant effects in humans is still up in the air.

[aLurker]

So according to my calculations (which I implore you all to double-check) a dose as low as 5 mg per day of Deprenyl might actually be harmful, at least in the long run. ~0.1-2.5 mg/day seems to be far superior health wise.
Of course one should bear in mind that these are studies on animals and not humans after all.

Ok, to continue my monologue about Deprenyl, sorry about the thread-jacking:
I had a quick peek at a study done with elderly (10-15 y.o.) dogs which were given 1mg/kg per day. That would give us an human equivalent dosage of 1*(20/37) mg/kg. Which amounts to 32 mg daily for an old 60 kg human. This indicates that my previous assessment that 5 mg/day had reason to be harmful might have been somewhat hasty since my impression is that dogs are closer to us humans than rats DNA-wise, even though these were old dogs obviously.

(Also I did some further investigating about the rat-studies and found this: "Doses used were 0.25, 0.50, and 1.0 mg/kg/injection (inj.), three times a week. Average life spans of animals were significantly longer in male rats given 0.25 and 0.5 mg/kg/inj.; however, rats given a 1.0 mg/kg dose began dying earlier than control rats"
So 0.25 or 0.50 or 1.0 times (3/7)*(6/37)*60kg gives us 1.0, 2.1 and 4.2 mg/day respectively, quite close to the previous statements about the rat-studies, but dogs should be closer relatives to us)

I don't really have a clue at what dosage Deprenyl becomes counter-productive for ones overall health, especially for someone young. A saw a chart with increasing dosage with age here on the forum somewhere but I couldn't find a source for it, if someone can find one please tell me. I trust Dr. Knoll knows far more than me about this subject and a low dose is probably better since he suggests 1 mg/day for humans from sexual maturity.

[chrono]

I don't know if it's reasonable to compare data from these two sets of studies. The 3x weekly dosage of the rat study may have been an important factor in the nature of its effect. And both studies relied on mortality data from animals administered to beginning when they were very old. But the numbers for rats seems to correlate pretty well anyway.

btw, unless you're calculating dosages for your own body weight, 70kg is pretty commonly used as an average. 60kg is on the low side.

[k10]

Preclinical investigations have shown that both rasagiline and its major metabolite, aminoindan (AI), exhibit neuroprotective properties. Rasagiline can increase the survival of dopaminergic neurones,^[17] protect against glutamate-induced neurotoxicity^[18] and block neurotoxicity in the MPTP model of PD.^[19] The neuroprotective potential of AI is also demonstrated via its antiapoptotic activity.^[20] As rasagiline also induces neuroprotection in cell cultures lacking MAO-B,^[21] at least some of rasagiline's neuroprotective potential appears to be mediated by a mechanism other than MAO-B inhibition. Further to this, the S-enantiomer of rasagiline also demonstrates neuroprotective potential, while showing minimal MAO-B inhibitory activity.^[20,22,23]

There is insufficient evidence to prove that any current antiparkinsonian agent can contribute such neuroprotective/disease-modifying effects in the clinical setting.^[24] However, as this is a key target for PD therapies, a recent study included a delayed-start design to evaluate the effect of rasagiline on disease progression, and this produced some promising preliminary results.^[25]

Another important characteristic of rasagiline is that its metabolites do not appear to possess any detrimental characteristics and as discussed above, AI may even offer a therapeutic benefit.^[20,21,26] This is in contrast to the amphetamine metabolites of the MAO-B inhibitor selegiline, which have neurotoxic properties that may be related to safety concerns observed in the clinic (high blood pressure, increased heart rate and insomnia).^[27-29]

[k10]

Rasagiline improves learning and memory in young healthy rats.
Wong FK, Lee SH, Atcha Z, Ong AB, Pemberton DJ, Chen WS.

Abstract
The effect of rasagiline on learning and memory in Lister-Hooded rats was investigated in this study. Two cognitive tests were used: a 24-h temporal deficit novel object recognition test and a modified water maze task. Rasagiline (0.3 and 1 mg/kg) was administered subcutaneously 15 min before the cognitive tests. In a novel object recognition test, rasagiline treatment enhanced object recognition memory. A small effect was observed with 0.3 mg/kg rasagiline; at 1 mg/kg, rasagiline-treated animals spent twice as much time exploring the novel object. On the water maze test, the use of an on-demand platform allowed adjustment of the difficulty of this spatial learning task. This enabled the detection of a small positive effect of rasagiline (1 mg/kg) on spatial learning, which was not observed in earlier reports. For the first time, our study has showed the procognitive effect of rasagiline in young healthy rats. On the basis of these findings, a monoamine oxidase-B inhibitor would seem to be a potential symptomatic treatment for cognitive impairments affecting patients with neurodegenerative disorders.

Edited by k10, 01 August 2010 - 01:14 AM.

[k10]

Studies of Selegiline for ADD, which may also support the use of rasagiline since they work by the same mechanism of inhibiting MAO-B:

Selegiline:

Quote:

There is evidence suggesting a role for dopamine in attention-deficit/hyperactivity disorder (ADHD). Pharmacological treatments that act on the dopamine system have been successful in reducing ADHD symptoms. However, unlike traditional stimulants (i.e., methylphenidate), selegiline is a monoamine oxidase inhibitor (MAOI) that has been shown to reduce ADHD symptoms without producing undesirable side effects. In this study using a randomized, double- blind, placebo-controlled, crossover design, cognitive tasks and behavioral rating scales were administered to measure the effectiveness of selegiline in treating different symptoms of ADHD in 11 children aged 6-13. Results indicate that selegiline may target specific symptoms of ADHD including: sustained attention, the learning of novel information, hyperactivity, and peer interactions. Because the drug was not associated with negative side effects and did not specifically reduce symptoms of impulsivity, selegiline may be a preferred treatment for individuals who present with the primarily inattentive subtype of ADHD.

Quote:

OBJECTIVES: The aim of this study was to examine the selegiline treatment compared to methylphenidate (MPH) in children and adolescents with attention deficit hyperactivity disorder (ADHD). METHOD: Forty subjects, aged 6-15 years, boys and girls, who were diagnosed as having ADHD, using the criteria of the Diagnostic and Statistical Manual of Mental Disorders- Fourth Edition (DSM-IV), were randomly assigned to receive either selegiline or MPH for 60 days. Treatment outcomes were assessed using the Attention Deficit Hyperactivity Scale (ADHS) administered at baseline and on days 14, 28, 42, and 60 following the commencement of treatment. Side effects were also rated. RESULTS: There were no significant differences between sex, age, weight, and ethnicity of participants in the 2 groups. Both groups showed a significant improvement over the 60 days of treatment resulting from the teachers' and parents' ADHS scores across the treatment. CONCLUSION: Following the trial, MPH did not effect greater mean improvement as a result of the parents' or teachers' ADHS scores than selegiline. Thus, selegiline appears to be effective and well tolerated for ADHD in children and adolescents. Quote: Attention deficit hyperactivity disorder (ADHD) is a common disorder of childhood that affects 3% to 6% of school-age children. Conventional stimulant medications are recognized by both specialists and parents as useful symptomatic treatment. Nevertheless, approximately 30% of ADHD children treated with them do not respond adequately or cannot tolerate the associated adverse effects. Such difficulties highlight the need for alternative safe and effective medications in the treatment of this disorder. Selegiline is a type B monoamine oxidase inhibitor (MAOI) that is metabolized to amphetamine and methamphetamine stimulant compounds that may be useful in the treatment of ADHD. The authors undertook this study to further evaluate, under double-blind and controlled conditions, the efficacy of selegiline for ADHD in children. A total of 28 children with ADHD as defined by DSM IV were randomized to selegiline or methylphenidate dosed on an age and weight-adjusted basis at selegiline 5 mg/day (under 5 years) and 10 mg/day (over 5 years) (Group 1) and methylphenidate 1 mg/kg/day (Group 2) for a 4-week double-blind clinical trial. The principal measure of the outcome was the Teacher and Parent ADHD Rating Scale. Patients were assessed by a child psychiatrist at baseline, 14 and 28 days after the medication started. No significant differences were observed between the two protocols on the Parent and Teacher Rating Scale scores. Although the number of dropouts in the methylphenidate group was higher than in the selegiline group, there was no significant difference between the two protocols in terms of the dropouts. Decreased appetite, difficulty falling asleep and headaches were observed more in the methylphenidate group.The results of this study must be considered preliminary, but they do suggest that selegiline may be beneficial in the treatment of ADHD. In addition, a tolerable side effect profile may be considered as one of the advantages of selegiline in the treatment of ADHD.

Quote:

Plasma monoamines and monoamine metabolites were assessed before and during selegiline treatment in adults with attention deficit/hyperactivity disorder (ADHD). Selegiline, at low dose, is a selective monoamine oxidase inhibitor type B (MAOI-B). After 2-week placebo baseline, 36 ADHD adults were randomized to 6-week placebo or 20 mg/day or 60 mg/day selegiline, followed by 2-week posttreatment placebo. Twenty-seven subjects continued into a 6-week 20-mg/day or 60-mg/day selegiline period. Behavioral variables included self-rated scores on the Conners' Abbreviated Teacher Rating Scale (Conners-ATRS) and performance on a Continuous Performance Task (CPT). Plasma samples were assayed for amines (dopamine, norepinephrine, epinephrine), precursor (DOPA), and metabolites (HVA, DOPAC, DHPG, normetanephrine, metanephrine, 5-HIAA). Selegiline produced dose-dependent changes in monoamine metabolites and DOPA plasma levels. Dopaminergic indices were associated with ADHD symptom severity (Conners-ATRS) and noradrenergic indices with CPT performance. Serotonergic metabolism, challenged by selegiline, correlated with clinical changes. These findings support a multisystem dysfunction underlying ADHD pathophysiology.

Quote:

We conducted a double-blind placebo-controlled crossover study to assess the efficacy of deprenyl for attention deficit hyperactivity disorder (ADHD) in children and adolescents with comorbid Tourette's syndrome (TS). Twenty-four subjects (21 boys, 3 girls; mean age 12 years) were enrolled at two sites (University of Rochester and Baylor College of Medicine). The design included two 8-week treatment periods separated by a 6-week washout period. The primary outcome measures for ADHD and tic severity were total scores on the DuPaul Attention Deficit Hyperactivity Scale (DADHS) and the Yale Global Tic Severity Scale (YGTSS). Fifteen subjects completed the study. The primary analysis revealed no statistically significant beneficial effect of deprenyl on the DADHS (mean improvement 1.3; 95% CI, -2.7 to 5.3; p = 0.50). Further post-hoc analyses revealed, however, that the effect of deprenyl in the first period was substantial (p = 0.02). There was a marginally statistically significant beneficial effect of deprenyl on the YGTSS total score (p = 0.06). Deprenyl may improve both ADHD and tics in children with TS and warrants further study.

Quote:

Clinical effects of high-dose and low-dose selegiline treatment were examined in 24 adults with attention deficit hyperactivity disorder (ADHD). The study used a double-blind randomized three-arm parallel-groups design with a 2-week placebo baseline followed by 6 weeks of treatment (placebo, 20 mg/day, or 60 mg/day selegiline) and then by 2 weeks of placebo post-treatment. A two-way repeated measures analysis of variance (ANOVA) showed no Drug x Time interaction and no main effect of Drug on severity of ADHD symptoms as self-rated by the subjects on the Conners Abbreviated Teacher Rating Scale (Conners ATRS). There was a significant effect of Time, indicating decreased ADHD symptom severity scores in all three groups. Selegiline treatment was not more effective than placebo. Side effects were more severe in the high-dose selegiline group than in either of the other groups. These preliminary results must be interpreted with caution because of methodological limitations in terms of sample size, patient population selection, and measurement tools.

Quote:

While central nervous system stimulants usually improve attention deficit hyperactivity disorder (ADHD) associated with Tourette's syndrome, they often exacerbate tics and can produce other potentially serious complications. Because deprenyl may have a stimulatory effect and monoamine oxidase inhibitors have been shown to ameliorate hyperactive behavior, we studied this drug in children with the Tourette's syndrome-ADHD combination. Twenty-nine patients, 25 boys and four girls, with a mean age of 11.2 years (range, 6 to 18 years) and duration of symptoms for an average of 6.2 years (range, 1 to 13 years), were enrolled in this open trial after they became refractory to conventional treatments for ADHD. The average duration of treatment with deprenyl was 6.7 months (range, 3 to 15 months) and the average daily dose was 8.1 mg/d (range, 5 to 15 mg/dL). Twenty-six of all patients (90%) reported clinically meaningful improvement in their ADHD (score > or = 2 on a scale of 0 to 4), with the mean global improvement rated at 2.6. There were no serious adverse side effects and only two patients noted exacerbation of their tics. Deprenyl appears to be a safe and effective treatment of ADHD in patients with Tourette's syndrome.

Comments:
- Selegiline is as effective as methylphenidate overall
- Selegiline is significantly effective for inattention
- Selegiline is not significantly effective for hyperactivity/impulsivity
- Selegiline is associated with a lower rate of side effects than methylphenidate
- Selegiline is effective for ADHD with comorbid tics
- Selegiline might not be effective for adults

Source:
http://www.addforums...?t=57501&page=3

Edited by k10, 01 August 2010 - 01:25 AM.

[chrono]

^^ Did you ever end up taking this? I thought you had a script all ready in June?

[unregistered_user]

Yea, any updates from the OP?

[e Volution]

^^ Did you ever end up taking this? I thought you had a script all ready in June?

Yea, any updates from the OP?

Umm what they said...

Edited by e Volution, 04 April 2011 - 04:17 AM.