11 replies to this topic

[NeuroNootropic]

I'm currently taking 5 mg of Selegiline every Monday, Wednesday and Friday for depression, low energy, and low motivation. I'm trying to decrease my sleep time from 12 hours to something more normal like 8-9 hours. In the past, I've taken Rasagiline 1 mg everyday and it was very helpful for low energy, low motivation, apathy, and it decreased my total sleep time to 8-9 hours. But with Selegiline, it's completely different. I haven't taken Rasagiline for more than a year as it's extremely expensive ($500 for 60 1 mg tablets) and I was only able to get it through my insurance. I also haven't taken Selegiline for more than a year. I've been taking it for about 4 weeks now and the first 2 weeks I was extremely tired. I couldn't even read because I kept losing focus. Rasagiline doesn't have this side effect.

 

Rasagiline also doesn't affect the alpha-adrenoreceptors and doesn't increase the expression of DAT. With Rasagiline, modafinil was much more powerful and even a cup of black tea was stimulating whereas with Selegiline modafinil is still the same (weak) and caffeine has little to no effect.

 

In the 3rd week of taking Selegiline I noticed a small increase in motivation, but the by the 4th week it was gone. Does Selegiline transiently increase dopamine? Rasagiline worked without tolerance it seems. It continued working until I ran out.

 

Here's the article on Selegiline's effects on DAT expression:

 

Amphetamine-induced increase in striatal extracellular dopamine level was attenuated by one day and by chronic (21 days) treatment with selegiline (0.25 mg kg−1, s.c.).
Striatal levels of DAT were elevated after 1 and 21 days treatment with selegiline, but were not affected by clorgyline, rasagiline, nomifensine or amphetamine.
The increase in DAT expression, and attenuation of amphetamine-induced dopamine release, were not accompanied by a change in [3H]-dopamine uptake in synaptosomes of selegiline-treated animals.
The results suggest that a reversible inhibition of dopamine uptake occurs following chronic low dose selegiline treatment in vivo which may be mediated by an increase in endogenous MAO-B substrates such as 2-phenylethylamine, rather than by the inhibitor molecule or its metabolites. Increased DAT expression appears to be a special property of the selegiline molecule, since it occurs after one low dose of selegiline, and is not seen with other inhibitors of MAO-A or MAO-B. The new DAT molecules formed following selegiline treatment appear not to be functionally active.

The increases in DAT levels that we observed appear to be in contradiction to the proposed reduction in functional activity of the transporter, but activity of the transporter in vivo is dependent on both number of active transporter molecules as well as the presence of endogenous inhibitors, e.g. PEA. Although we found an increase in number of transporter molecules by selegiline, the newly synthesized molecules may be internalized or otherwise inactive, or their potential to enhance dopamine uptake may be inhibited by endogenous PEA.

→ source (external link)

 

Personally I haven't noticed any withdrawal symptoms from neither Selegiline nor Rasagiline, but I have noticed that certain substances no longer affect me the same as they did in the past. For example, Rhodiola in the first 2-3 weeks was amazing, it would greatly reduce anhedonia, increase energy, reduce fatigue, reduce sleep time to around 8 hours, increase the ability to feel emotions (especially from music), give me the ability to laugh at funny things (I haven't been able to laugh for more than 6 years now), increase motivation, and other benefits, but now Rhodiola is barely noticeable. It's like taking a sugar pill. Same thing with Wellbutrin, except with Wellbutrin the side effects are still there, but the benefits have decreased.

 

So now I'm wondering if Selegiline is responsible for these changes. Is this reversible? How would I restore homeostasis?

[Flex]

Good question, I dont know.

Form my laymans knowledge and opinion, I guess there will be a compensation by the body. Like in the case of mall tardive dyskinesias (caused by antipsychotics or L-dopa ? ) which also get compensated up to a certain severity. 

Edited by Flex, 10 May 2015 - 05:15 PM.

[BieraK]

I'm thinking in memantine. I've read anecdotes about a high reversal in tolerance to things like caffeine, cannabis, stimulants, green tea.

The other important thing is tyrosine hydroxilase, this enzyme is dowregulated by selegiline according to two studies, search in the forum I've posted that studies in the past.

For tyrosine hydroxylase downregulation I'm thinking in two things:
9 Methyl Beta Carboline (Not available for now, THT is gone :(...)

Lithium Orotate... I'm want to try this combo of lithium orotate+selegiline... Selegiline is very cheap in my country and not requires prescription the 30x10mg tablets costs approximately 25 dollars


 

[zaratoo]

Increased DAT expression appears to be a special property of the selegiline molecule, since it occurs after one low dose of selegiline, and is not seen with other inhibitors of MAO-A or MAO-B. The new DAT molecules formed following selegiline treatment appear not to be functionally active.

The increases in DAT levels that we observed appear to be in contradiction to the proposed reduction in functional activity of the transporter, but activity of the transporter in vivo is dependent on both number of active transporter molecules as well as the presence of endogenous inhibitors, e.g. PEA. Although we found an increase in number of transporter molecules by selegiline, the newly synthesized molecules may be internalized or otherwise inactive, or their potential to enhance dopamine uptake may be inhibited by endogenous PEA.

 

 

So doesn't it mean that DAT increase causes no changes in DA levels and thus not a problem at all?
As for Rhodiola, I saw frequently reported it loses its 'magic' for people. Also physically active people (and probably with low-toxic diets) don't feel it that much or at all.

And one more (which was my initial impulse to post actually). 500USD for 60 tabs is indeed absurdly expensive. ADC has it for pennies in comparison. More of that a lot of Russian phamasies (and here I mean fully official channel where there's lots of additional costs) here have branded Azilect and it's ~$90 per 30tabs, which I believe is pricey, but still substantially cheaper.

That being said, if Ras works for you w/o any issues but price, why not to give an Indian generic a chance? That seem to me more useful for yourself, than hypotesising on why is Sel not good for you. The latter could be useful for board tho)

Aslo I myself never 'believed' in need in Ras and some time and still hope to try Sel. But if I eventually place my order, I'll get both of course.

And a little more about sleep length. I take 62,5mcg of Mirapex (Pramipexole) at 22:30 and am wide awake by 7:00 or even earlier. Don't know if it's good, but no morning sleepiness for sure. Did not do it for too long - it's my 12th day.

Cheers! 

 

 

 

[Metagene]

I'm thinking in memantine. I've read anecdotes about a high reversal in tolerance to things like caffeine, cannabis, stimulants, green tea.

The other important thing is tyrosine hydroxilase, this enzyme is dowregulated by selegiline according to two studies, search in the forum I've posted that studies in the past.

For tyrosine hydroxylase downregulation I'm thinking in two things:
9 Methyl Beta Carboline (Not available for now, THT is gone :(...)

Lithium Orotate... I'm want to try this combo of lithium orotate+selegiline... Selegiline is very cheap in my country and not requires prescription the 30x10mg tablets costs approximately 25 dollars

I'm not certain this combination would be necessary or desirable.

Effect of repeated treatment with high doses of selegiline on behaviour, striatal dopaminergic transmission and tyrosine hydroxylase mRNA levels


"As regards dopamine, other groups observed that chronic but not acute administration of selegiline increased extracellular dopamine in the striatum (Lamens- dorf et al. 1996). These authors used much lower doses (0.25 mg/kg each), so that chronic treatment apparently did not lead to any negative feedback on dopamine syn- thesis. The observation that the basal concentrations of dopamine were not increased in our own experiments in spite of a probably long-lasting inhibition of MAO-B seems remarkable and may be explained by a down-regulation of tyrosine hydroxylase induced by the large dose (see below).

The experiments studying TH mRNA were performed after a longer selegiline pretreatment than those studying extracellular dopamine, since it seemed more likely to observe more pronounced alterations in TH mRNA than after a short pretreatment period.

The results with TH mRNA supplement the findings on dopaminergic neurotransmission described. There were no changes in TH mRNA levels after an acute treatment (Figs. 4, 5), suggesting that the enhanced extracellular dopamine is due to the inhibition of MAO-B and/or the increase in dopamine release by (-)-amphetamine and (-)-metamphetamine. After acute treatment, dopamine synthesis might be altered, but only at the enzyme levels. Chronic treatment led to a decrease of TH mRNA levels. Similar results were found by Lamensdorf and Finberg (1997) who observed a significant reduction in TH activity even only after 21 days of administration of a lower dose (0.25 mg/kg). In contrast, Vrana et al. (1992) showed an enhanced expression after 21 days. These discrepancies are probably due to the fact that they applied an even lower dose of 0.1 mg/kg of selegiline.

Thus our results support an earlier conclusion of Lamensdorf and Finberg (1997) that the decreased level of TH mRNA is the result of a feedback-mechanism as a consequence of primarily increased dopamine levels after repeated selegiline administration which would lead to an accumulation of dopamine without this counter-regulation."

https://docs.google....sp=docslist_api

Edited by Metagene, 11 May 2015 - 03:03 PM.

[β-Endorphin]

Considering that the increase in DAT expression seems to be a compensatory mechanism of the brain to deal with increases extracellular dopamine concentrations, I would put my money on it being reversible. I believe that if you stop taking selegiline, DAT concentrations would return to normal. But increased DAT expression isn't necessarily a bad thing. For example, reduced DAT expression is found in people with schizophrenia and brain injuries. Additionally, DAT expression is reduced with aging. So, selegiline may(theoretically) be acting as an anti-aging agent by increasing DAT expression! Either way, I wouldn't worry too much about this. I imagined Selegiline may be causing cross tolerance, but it is natural for the brain to maintain homeostasis by countering the effects of the drug being taken. I wouldn't try to modify your brain chemistry in an effort to "chase" whatever effects the other herb gave you if I were you. But again, if you want to, stopping the Selegiline should theoretically reverse the increase in DAT expression.

[Metagene]

Considering that the increase in DAT expression seems to be a compensatory mechanism of the brain to deal with increases extracellular dopamine concentrations, I would put my money on it being reversible. I believe that if you stop taking selegiline, DAT concentrations would return to normal. But increased DAT expression isn't necessarily a bad thing. For example, reduced DAT expression is found in people with schizophrenia and brain injuries. Additionally, DAT expression is reduced with aging. So, selegiline may(theoretically) be acting as an anti-aging agent by increasing DAT expression! Either way, I wouldn't worry too much about this. I imagined Selegiline may be causing cross tolerance, but it is natural for the brain to maintain homeostasis by countering the effects of the drug being taken. I wouldn't try to modify your brain chemistry in an effort to "chase" whatever effects the other herb gave you if I were you. But again, if you want to, stopping the Selegiline should theoretically reverse the increase in DAT expression.

The study above noted chronic selegiline administration only caused a temporary increase in extracellular dopamine.

"In conclusion, repeated administration of selegiline leads to behavioural sensitization independent of altered dopamine levels. In addition, it leads to a decrease, probably due to a down-regulation, of dopamine turnover and tyrosine hydroxylase."

http://www.ncbi.nlm....ubmed/11862330/

Compare the effects of high dose Methylphenidate on DAT expression.

http://www.ncbi.nlm....les/PMC4017736/

Edited by Metagene, 11 May 2015 - 06:31 PM.

[NeuroNootropic]

 

Increased DAT expression appears to be a special property of the selegiline molecule, since it occurs after one low dose of selegiline, and is not seen with other inhibitors of MAO-A or MAO-B. The new DAT molecules formed following selegiline treatment appear not to be functionally active.

The increases in DAT levels that we observed appear to be in contradiction to the proposed reduction in functional activity of the transporter, but activity of the transporter in vivo is dependent on both number of active transporter molecules as well as the presence of endogenous inhibitors, e.g. PEA. Although we found an increase in number of transporter molecules by selegiline, the newly synthesized molecules may be internalized or otherwise inactive, or their potential to enhance dopamine uptake may be inhibited by endogenous PEA.

 

 

So doesn't it mean that DAT increase causes no changes in DA levels and thus not a problem at all?
As for Rhodiola, I saw frequently reported it loses its 'magic' for people. Also physically active people (and probably with low-toxic diets) don't feel it that much or at all.

And one more (which was my initial impulse to post actually). 500USD for 60 tabs is indeed absurdly expensive. ADC has it for pennies in comparison. More of that a lot of Russian phamasies (and here I mean fully official channel where there's lots of additional costs) here have branded Azilect and it's ~$90 per 30tabs, which I believe is pricey, but still substantially cheaper.

That being said, if Ras works for you w/o any issues but price, why not to give an Indian generic a chance? That seem to me more useful for yourself, than hypotesising on why is Sel not good for you. The latter could be useful for board tho)

Aslo I myself never 'believed' in need in Ras and some time and still hope to try Sel. But if I eventually place my order, I'll get both of course.

And a little more about sleep length. I take 62,5mcg of Mirapex (Pramipexole) at 22:30 and am wide awake by 7:00 or even earlier. Don't know if it's good, but no morning sleepiness for sure. Did not do it for too long - it's my 12th day.

Cheers! 

 

 

I used to do HIIT 3x a week when I was taking Rhodiola and it still had its magic. I now lift weights 4x a week and Rhodiola barely does anything. Is there a large difference between the effects of HIIT and resistance training on the brain? I haven't seen any studies regarding this.

 

ADC has rasagiline, but it's still expensive for me. Also, I don't know if I can trust the quality of Indian generic drugs. Plus, ADC charges a flat $25 shipping fee which is ridiculous. I'd have to buy more than a year's supply to compensate for the shipping fee.

 

Your reaction to pramipexole is paradoxical, but then again you're at a low dose. Most people who take it have sedation in the first week or two because it hits the autoreceptors. A word of warning though, be careful with this drug, some people have found it to cause anhedonia upon withdrawal. 

 

It's been more than 2 weeks now, any tolerance issues or side effects regarding mirapex?

 

 

I'm thinking in memantine. I've read anecdotes about a high reversal in tolerance to things like caffeine, cannabis, stimulants, green tea.

The other important thing is tyrosine hydroxilase, this enzyme is dowregulated by selegiline according to two studies, search in the forum I've posted that studies in the past.

For tyrosine hydroxylase downregulation I'm thinking in two things:
9 Methyl Beta Carboline (Not available for now, THT is gone :(...)

Lithium Orotate... I'm want to try this combo of lithium orotate+selegiline... Selegiline is very cheap in my country and not requires prescription the 30x10mg tablets costs approximately 25 dollars

I'm not certain this combination would be necessary or desirable.

Effect of repeated treatment with high doses of selegiline on behaviour, striatal dopaminergic transmission and tyrosine hydroxylase mRNA levels


"As regards dopamine, other groups observed that chronic but not acute administration of selegiline increased extracellular dopamine in the striatum (Lamens- dorf et al. 1996). These authors used much lower doses (0.25 mg/kg each), so that chronic treatment apparently did not lead to any negative feedback on dopamine syn- thesis. The observation that the basal concentrations of dopamine were not increased in our own experiments in spite of a probably long-lasting inhibition of MAO-B seems remarkable and may be explained by a down-regulation of tyrosine hydroxylase induced by the large dose (see below).

The experiments studying TH mRNA were performed after a longer selegiline pretreatment than those studying extracellular dopamine, since it seemed more likely to observe more pronounced alterations in TH mRNA than after a short pretreatment period.

The results with TH mRNA supplement the findings on dopaminergic neurotransmission described. There were no changes in TH mRNA levels after an acute treatment (Figs. 4, 5), suggesting that the enhanced extracellular dopamine is due to the inhibition of MAO-B and/or the increase in dopamine release by (-)-amphetamine and (-)-metamphetamine. After acute treatment, dopamine synthesis might be altered, but only at the enzyme levels. Chronic treatment led to a decrease of TH mRNA levels. Similar results were found by Lamensdorf and Finberg (1997) who observed a significant reduction in TH activity even only after 21 days of administration of a lower dose (0.25 mg/kg). In contrast, Vrana et al. (1992) showed an enhanced expression after 21 days. These discrepancies are probably due to the fact that they applied an even lower dose of 0.1 mg/kg of selegiline.

Thus our results support an earlier conclusion of Lamensdorf and Finberg (1997) that the decreased level of TH mRNA is the result of a feedback-mechanism as a consequence of primarily increased dopamine levels after repeated selegiline administration which would lead to an accumulation of dopamine without this counter-regulation."

https://docs.google....sp=docslist_api

 

 

So from this it seems that 0.1 mg/kg doesn't decrease TH but actually increases it. What dosage would that translate to for humans? Cordyceps increases TH, but its beneficial effects were blunted by Selegiline when I took it.

 

Cordyceps militaris is a popular medicinal mushroom, and has received extensive attention for medical application because of its various physiological activities. However, there is limited information about the function of Cordyceps militaris on dopaminergic system. This study has attempted to evaluate the effect of cultured fruiting bodies of Cordyceps militaris extract (CME) on the expression of the tyrosine hydroxylase (TH) gene in PC12 cells and rat brain and stomach. Related mRNA levels were determined by the RT-PCR. Protein levels were measured by Western blot and immunohistochemistry. Our results demonstrated CME induced TH gene expression both in vitro and in vivo. Treatment of 10 µg/ml and 20 mg/kg CME to PC12 cells and rat cells yielded significant increases of TH protein levels. Significantly, TH immunoreactive neurons were detected not only in the brain but also in the stomach. TH-immunohistochemical staining was markedly enhanced in animals treated with CME compared to those in the untreated control. These results suggest that CME can upregulate the dopaminergic (DArgic) system, and may contribute to neuroprotection in neurodegenerative diseases.

→ source (external link)

[Metagene]

I have dyscalculia so check my math.

0.1x6 = 0.6/37 = 0.01621621621= 0.02mg

HED = 0.02mg/kg

70kg human = 1.4mg

http://www.longecity...animal-studies/

[Flex]

I have dyscalculia so check my math.

0.1x6 = 0.6/37 = 0.01621621621= 0.02mg

HED = 0.02mg/kg

70kg human = 1.4mg

http://www.longecity...animal-studies/

 

For me, complete fine

Edited by Flex, 28 May 2015 - 12:38 AM.

[Metagene]

Thanks Flex.

[zaratoo]

 

Your reaction to pramipexole is paradoxical, but then again you're at a low dose. Most people who take it have sedation in the first week or two because it hits the autoreceptors. A word of warning though, be careful with this drug, some people have found it to cause anhedonia upon withdrawal. 

 

It's been more than 2 weeks now, any tolerance issues or side effects regarding mirapex?

 

 

I believe DA is sedative by itself (unlike its metabolites NE and E), so people taking it in normal dose and through the day should feel somnolence. When I take it before bed it certainly helps to fall asleep, but wakes you up few hours later. People at some bb boards called it a "rebound" without mush details. I took another dose at about 4am and didn't have unpleasant wakefulness until the morning. Now I don't do so. Not sure why, mostly playing around with stuff..

As for progress in action of Pramipexole, it began to be felt obviously much later, than two weeks, month maybe. Now If I even just take too late in the evening I get "sad morning", but rather wonderful early day, probably too even euphoric. And caffeine feels more at euphoric side, than at stimulating. Wouldn't say how long this state lasts though, because I do IF and a lot of things change, when I break my fast at ~14:00. I should note that although this rebound hyperthymia feels good, I'd not say I'm satisfied.. And this sad mood is one of reasons I don't take the second dose this days. Tonight I won't do it at all to see how I'll sleep. Potentially good drug, but I still didn't find the way to get the most of it.

ADC shipping is an obstacle for sure. I must order for 100+ USD to get it have any sense. Still hope to have their Sel/Ras (and want to try albuterol for bb purposes)..