54 replies to this topic

[peakplasma]

Well, I just can't understand why you're behaving so aggressively for no apparent reason. I'm not qualified to explain it to you but your MD can explain it to you!

I have a rudimentary understanding (well beyond layman) but it is only a 0.1% of the understanding my MD has who specializes in dopaminergic therapy and Parkinsonism.

Given that you don't have a background in medicine/pharmacology, can't you conceive of the possibility that there are possible risks you are not aware of?

Are you really so certain that you would risk dopamine dysregulation or secondary parkinsonism?

[peakplasma]

I never not warned of possible risks. I mentioned the estimation of an ideal dose of around 10mg/d or lower. The latter preferably.

How exactly are you qualified to estimate this?

[KoolK3n]

Well, I just can't understand why you're behaving so aggressively for no apparent reason. I'm not qualified to explain it to you but your MD can explain it to you!

Yes, I'm "aggressive". Get over it?
So far this has basically been your response:

Given that you don't have a background in medicine/pharmacology, can't you conceive of the possibility that there are possible risks you are not aware of?

I've taken multiple AP science classes in HS. I'm in the midst of obtaining my Pharmacy Technician certificate. I'm undergoing my pursuit of a neuroscience major. I've been invested in nootropic pharmacology for well over 2 years. I've been active on other forums for a long time. I'm not new to this at all. I had a good friend hospitalized and put in a psych ward for pushing the boundaries to far. You can bet your ass I'm aware of the risks.

Are you really so certain that you would risk dopamine dysregulation or secondary parkinsonism?

My goal is to limit that possibility to a near 0% and maximize nootropic potential.

[peakplasma]

Well, I just can't understand why you're behaving so aggressively for no apparent reason. I'm not qualified to explain it to you but your MD can explain it to you!

Yes, I'm "aggressive". Get over it?
So far this has basically been your response:

Given that you don't have a background in medicine/pharmacology, can't you conceive of the possibility that there are possible risks you are not aware of?

I've taken multiple AP science classes in HS. I'm in the midst of obtaining my Pharmacy Technician certificate. I'm undergoing my pursuit of a neuroscience major. I've been invested in nootropic pharmacology for well over 2 years. I've been active on other forums for a long time. I'm not new to this at all. I had a good friend hospitalized and put in a psych ward for pushing the boundaries to far. You can bet your ass I'm aware of the risks.

Are you really so certain that you would risk dopamine dysregulation or secondary parkinsonism?

My goal is to limit that possibility to a near 0% and maximize nootropic potential.

This is a joke.

You're either a troll or you need mental help.

An unfinished pharmacy tech certification and a few high school AP classes? This is your qualification to prescribe dopaminergic therapy?

Go see your doctor before you do some irreversible damage.

EDIT: Also, please stop recommending this to others and telling them it is safe. You are going to hurt someone.

Edited by peakplasma, 20 April 2013 - 01:39 AM.

[Healthy Tony]

Been on this combo for 3 days now. No apparent dopamine issues or gay thoughts. :p I'll let you guys know if I experience any issues.

[KoolK3n]

This is a joke.

You're either a troll or you need mental help.

An unfinished pharmacy tech certification and a few high school AP classes? This is your qualification to prescribe dopaminergic therapy?

If calling me names makes you feel better, then go ahead.
Yes I agree those credentials I mentioned aren't significant, but I'm pretty sure that's more than the majority of the members. Not to gloat as if it's anything to gloat about but hopefully you get my point (which you probably don't). Ex: A noobie inexperienced with nootropics asks for advice and over a dozen instantly recommend jumping on the advanced research chemicals such as PRL or NSI or Dihexa or BPAP or whatever. Those should be reserved to relatively experienced users.

No, I did not prescribe anyone to take anything. I've said time and time again that this combo MAY work and warrants extreme caution because it's somewhat uncharted territory.

Go see your doctor before you do some irreversible damage.

Really? That's really interesting since I just saw in the BPAP thread that you agreed to participate in the group buy of an RC (Research chemical). A research chemical?! And your yelling at me? Lol.

EDIT: Also, please stop recommending this to others and telling them it is safe. You are going to hurt someone.

I never said it was safe. I said ACCORDING TO (Please understand the word according to) others from their experiences on other forums, it looks like when all the available data is public. It SEEMS like anyting above 10mg/d seems to blunt any cognitive enhancing effect. But as my disclaimer, I've pointed out that my opinions change on a regular basis as new data is available for analysis.

Btw, just this thread ALONE, two people have already told us they are on this combo and appear to have retained their sexual preferences. Refer to post #17 and #35 of this thread.

Note: ScienceGuy if you're reading this. I finally understand why CAPTIONING specific words is fun. Hopefully you don't mind me doing that every once in a while. Seems so empowering. And no that wasn't an insult.

Edited by KoolK3n, 20 April 2013 - 01:01 PM.

[peakplasma]

One last time...

I'm not sure you fully appreciate the risks of the combination.

You are basing your risk assessment ACCORDING TO a paucity of anecdotal experiences on forums - this is critically flawed.

You may not be aware of the consequences while you are young and healthy but you will regret it when you are older.

Your MD can explain this all to you but honestly, there are so many risks you should count yourself lucky if all you do is "turn gay" - not that there's anything wrong with that.

---

I wish you the best of luck and I do hope you see your doctor before you do some irreversible damage.

[Passion]

PeakPlasma,

What form of selegeline do you take and in what dosage/frequency? I've read a few threads challenging its efficacy in various forms/mixtures (tablet/liquid, hcl/citric acid). Dr. Knoll originally recommended 1mg per day of Deprenyl but didn't mention the form he takes personally.

Here's one of those threads:
http://www.longecity...eprenyl-liquid/

I was really turned on to this idea of selegiline by reading Dr. Knoll's interviews and I really want to take this supplement I just don't know from where or what form!

Thanks for you input :D

[peakplasma]

I get the cheapest ones my insurance will cover! They are called APO-Selegiline; it is hcl and comes in 5mg tablets but I have also had success with the TEVA brand 5mg tablets.
I aim for 1.25mg every other day (eod) with a heavy meal but I also frequently miss doses - with no apparent side effects from skipped doses.

It is from a pharmacy but many years ago I ordered it from the internet in liquid and tablets but I didn't notice a difference in efficacy.

I think mine probably absorb the worst of any form available but they seem to work well enough. One day I have to try the patch.

[Reformed-Redan]

PeakPlasma,

What form of selegeline do you take and in what dosage/frequency? I've read a few threads challenging its efficacy in various forms/mixtures (tablet/liquid, hcl/citric acid). Dr. Knoll originally recommended 1mg per day of Deprenyl but didn't mention the form he takes personally.

Here's one of those threads:
http://www.longecity...eprenyl-liquid/

I was really turned on to this idea of selegiline by reading Dr. Knoll's interviews and I really want to take this supplement I just don't know from where or what form!

Thanks for you input :D

Check geoffpharmacy or alldaychemist. The APO-selegiline is from New Zealand and the quality should be good. I took a chance and got the Intas pharma one's.

As to curing tolerance. It's unlikely that you can cheat homeostasis or else you'll end up in the bin. Thank God for homeostasis. I think Zinc and a lot of exersize will counter any significant tolerance (receptor downregulation.)

[Passion]

I think I'll go with ADC although I have to say, it's super sketchy that they require direct bank account # and routing #.

[peakplasma]

This might not matter but APO-Selegiline is actually from Canada not New Zealand.

APO refers to APOTEX which is an Ontario based pharmaceutical company that specializes in producing generics drugs. It is very popular here and if you've ever filled a generic prescription in Canada there is a good chance it is APO!

[autopilot]

I have started taking ADC tablets 1.25mg a day (1/4 tablets). Started sublinguil but has made my skin under tongue sore. Was dr knolls recommendation 1mg a day oral? How you taking it?

I have started taking ADC tablets 1.25mg a day (1/4 tablets). Started sublinguil but has made my skin under tongue sore. Was dr knolls recommendation 1mg a day oral? How you taking it?

[Healthy Tony]

Check geoffpharmacy or alldaychemist. The APO-selegiline is from New Zealand and the quality should be good. I took a chance and got the Intas pharma one's.

As to curing tolerance. It's unlikely that you can cheat homeostasis or else you'll end up in the bin. Thank God for homeostasis. I think Zinc and a lot of exersize will counter any significant tolerance (receptor downregulation.)

Zinc and excercise? Is this from personal experience or scientific studies? I'm just curious, because I'm used to hearing people using NMDA anatagonists for the purposes of curving tolerance.

[Reformed-Redan]

Check geoffpharmacy or alldaychemist. The APO-selegiline is from New Zealand and the quality should be good. I took a chance and got the Intas pharma one's.

As to curing tolerance. It's unlikely that you can cheat homeostasis or else you'll end up in the bin. Thank God for homeostasis. I think Zinc and a lot of exersize will counter any significant tolerance (receptor downregulation.)

Zinc and excercise? Is this from personal experience or scientific studies? I'm just curious, because I'm used to hearing people using NMDA anatagonists for the purposes of curving tolerance.

Zinc upregulates TH. Exersize increases dopamine receptor density and increases the amount of dopamine receptors. Those are the best ways AFAIK to decrease tolerance. There are plenty of papers on this. Just type "dopamine and excersize or zinc" in google and you'll see.

[**DEACTIVATED**]

I think it's important to play it safe and keep doses of Selegiline low. I see a lot of users who are dosing 5mg/day or even 2mg/day which I just don't think is sustainable long-term especially for younger individuals. The cognitive benefits are there, but at the expense of what?

The difference between longevity and early death is a fine line: http://www.selegilin...ity-dosage.html

[Reformed-Redan]

I'd like to bring BPAP up again. I believe its safer than deprenyl, lasts longer and has a better profile in terms of safety. Its great for long term health and longevity.

[KoolK3n]

I think it's important to play it safe and keep doses of Selegiline low. I see a lot of users who are dosing 5mg/day or even 2mg/day which I just don't think is sustainable long-term especially for younger individuals. The cognitive benefits are there, but at the expense of what?

The difference between longevity and early death is a fine line: http://www.selegilin...ity-dosage.html

Positive effects were noticed at the used dosage between .25-2mg per kg by injection. Injection is 100% bioavailable. The lowest dose they used .25mg/kg translates to 20.5mg/d for me since I weigh roughly 82kg. And this was 100% BA instead of the 5.5% oral. Correct me if I'm wrong.

Edited by KoolK3n, 22 April 2013 - 11:22 PM.

[**DEACTIVATED**]

Well that's interesting.. So we basically have nothing to worry about because of the low bioavailability?

The study is referring to mega doses of the drug, right? Again, low doses doesn't seem like a bad idea

[static55]

thought I'd resurrect the thread.

Any ideas on how to reset one's tolerance?

The first 4 days of using selegiline (5mg a day), I woke up feeling fully refeshed after 7 hours of sleep (typical for me) as if I'd been awake for 2 hours. Hopping right out of bed as soon as I woke up absolutely was no challenge at all.

On the 5th day and afterwards:

I don't wake up anymore feeling as completely alert -- but still more alert than before. I use the snooze button much less often.

I can get sleepy during the day every once in a while, which is nothing out of the ordinary for me. It's just that it didn't happen at all the first 4 days on selegiline, except for very late at night.

I still feel that the selegiline has a positive influence on me. I don't tend to experience random cravings for stimulation (junk food, tv, etc) nearly as often and I exibit fewer hyperactive ADD-like behaviors (attempts to generate dopiminergic stimulation, I assume). I don't tend to get "worn out" from working all day. I'm more chill and relaxed. I also hit the snooze button after my alarm goes off much less than I used to.

I still feel happier in general and have more control over myself.

I kinda miss the initial magic, though. 30mg DXM along with 450mg magnesium glycinate once or twice a day doesn't seem to reset me back to my original set point.

The effects of selegiline remind me of the effects of intermittent fasting. For the first 4 days or so of intermittent fasting I had similar effects, perhaps even stronger, but on the 5th day, the effects largely disappeared and I haven't figured out how to bring them back.
 

I'll give memantine a shot once it arrived in the mail. Any other ideas? Perhaps using additional substances to antagonize the NMDA receptors in different ways? Perhaps my body is creating more MAO than usual to compensate for the selegiline? Is there a way to counteract that?

[noot_in_the_sky]

Have you try 9-me-Bc? It help me with the tolerance I develop to selegiline.

[BieraK]

Have you try 9-me-Bc? It help me with the tolerance I develop to selegiline.

What you say makes a lot of sense to me
Apparently the selegiline tolerance problems, are due to Tyrosine Hydroxilase downregulation or a decrease in activity.

http://www.ncbi.nlm..../pubmed/1350320

Chronic selegiline administration transiently decreases tyrosine hydroxylase activity and mRNA in the rat nigrostriatal pathway.
Abstract

Selegiline, a selective monoamine oxidase type B inhibitor, is beneficial in the treatment of Parkinson's disease. However, this beneficial effect is only transient, and patients must ultimately resort to treatment with standard levodopa therapy. We studied the effects of chronic selegiline treatment on the rat nigrostriatal pathway, to elucidate a neurochemical correlate for this adaptive clinical response. Selegiline treatment for 3, 7, 14, or 21 days decreased tyrosine hydroxylase (the enzyme that catalyzes the rate-limiting step in catecholamine biosynthesis) activity in the cell body regions (substantia nigra) of the nigrostriatal pathway. However, tyrosine hydroxylase activity measurements in the major terminal field region (corpus striatum) of the pathway did not correspond to those in the substantia nigra; in the corpus striatum, tyrosine hydroxylase activity was decreased at 3 and 7 days of treatment and recovered by 14 days. We tested whether the decrease in tyrosine hydroxylase activity was mediated by a decrease in tyrosine hydroxylase mRNA. Northern blot and RNA dot blot analyses (using a tyrosine hydroxylase-specific cDNA probe) of substantia nigra homogenates revealed a significant decrease in tyrosine hydroxylase mRNA at 3, 7, and 14 days of selegiline treatment, compared with controls. Conversely, after 21 days of selegiline, tyrosine hydroxylase mRNA levels were significantly higher (3-fold) than controls; this finding was not reflected in substantia nigra tyrosine hydroxylase activity. The 21-day increase in mRNA may be associated with the rebound in tyrosine hydroxylase activity observed in the corpus striatum. Thus, it is possible that the recovery in tyrosine hydroxylase activity in the corpus striatum is mediated through an increase in tyrosine hydroxylase protein transport from the substantia nigra to the corpus striatum and/or that the tyrosine hydroxylase enzyme exists in a more stabilized state during this period of time. These results demonstrate that monoamine oxidase type B-selective inhibitory doses of selegiline are capable of inducing transient decreases in tyrosine hydroxylase activity and tyrosine hydroxylase mRNA levels. Furthermore, these reversible effects may represent adaptive responses associated with pharmacological tolerance and the transient beneficial actions of this drug in Parkinson's disease.

 

 

 

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

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

The anti-parkinsonian drug selegiline is a monoamine oxidase B (MAO-B) inhibitor and a potential neuroprotective agent which facilitates dopaminergic transmission. Its metabolites (-)-amphetamine and (-)-metamphetamine might contribute to the pharmacological effects as they are also able to increase dopaminergic transmission and in addition might lead to behavioural sensitization after repeated administration. We investigated the effects of acute and repeated treatment with a high dose of selegiline on dopamine overflow in the striatum as well as on behaviour and on tyrosine hydroxylase (TH) mRNA levels in midbrain. Two experiments were performed. In the first one, rats were implanted with microdialysis probes into the striatum and received daily injections of selegiline (10 mg/kg, i.p.) for 1 or 8 days or a single dose of saline. In vivo microdialysis was carried out on days 1, 8 or 17 (after withdrawal of 9 days) to measure dopamine overflow. Motility was measured at the same time. In the second experiment, rats were injected daily with selegiline (10 mg/kg, i.p.) or saline over a time period of 6 weeks or only once before the brains were processed for in situ hybridization with a (35)S-radiolabelled probe for TH. Repeated treatment led to higher levels in motility scores than acute administration after administration of the same dose, indicating behavioural sensitization, which was still manifest after an interruption of 9 days in the supply of selegiline. In contrast, acute administration of selegiline increased dopamine levels to a similar degree as the same dose after subchronic treatment, with or without interruption of 9 days. The dopamine metabolite DOPAC was reduced by more than 50% after acute administration of selegiline and even more so on day 8 by the same dose, after repeated administration. The basal concentrations of dopamine (before challenge with selegiline) were not altered by the repeated administration, whereas the basal concentrations of DOPAC were decreased by more than 80% by the repeated administration of selegiline, suggesting a decrease in dopamine turnover. Acute administration did not have any influence on TH mRNA levels, whereas chronic treatment significantly reduced TH mRNA levels in substantia nigra and ventral tegmental area. 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.

 

 

-------------------------------------------------------------------------------------------------------------------------------------------------
 

and 9mbc increases the expresions of Tyrosine Hydroxylase...

http://www.ncbi.nlm....pubmed/21651332

 

Stimulation, protection and regeneration of dopaminergic neurons by 9-methyl-β-carboline: a new anti-Parkinson drug?
Abstract  

β-carbolines are potential endogenous and exogenous neurotoxins that may contribute to the pathogenesis of Parkinson's disease (PD). 9-methyl-β-carboline exhibits multimodal effects that could be beneficial in the treatment of PD. It shows stimulatory effects to dopaminergic neurons by increasing the expression of tyrosine hydroxylase and its transcription factors in pre-existing dopa decarboxylase immunoreactive neurons. Furthermore, 9-methyl-β-carboline has emerged as a substance with the rare property of a protective and regenerative/restorative potential for dopaminergic neurons by inducing gene expression of several neurotrophic factors and decreasing apoptotic cell signals. It reduces protein levels of α-synuclein and inhibits monoamine oxidase A and B. Finally, 9-methyl-β-carboline acts on multiple targets in the inflammatory cascade by inhibiting the proliferation of microglia, by decreasing chemotactic cytokines and by creating an anti-inflammatory environment in the CNS. This article summarizes our current knowledge of 9-methyl-carboline and discusses its potential role as a new drug for the treatment of PD.

 

 

 

Edited by Arsonista, 08 January 2015 - 09:51 PM.

[static55]

Interesting! The science behind all this stuff is new to me but I'm catching on bit by bit.

 

I haven't tried 9-me-Bc yet but I'll certainly be buying some soon. Until then I'll do some research and try out other stuff that increases the expression of tyrosine hydroxylase.

 

[static55]

I found a blog article that summarizes tyrosine / tyrosine hydroxylase nicely in laymans language. It might be a bit remedial for most folks here but I found it informative  (summary):

 

 

 

Does Tyrosine Supplementation Actually Work for ADHD? (part 2)
Can ADHD symptoms be alleviated by supplementing with the amino acid tyrosine?

...

To summarize the key points and suggestions which should be taken away from this the blog post:
Do not overdose on Tyrosine supplementation. For reference, a ballpark estimate on dosing is often somewhere around 500 to 1500 mg per day, but please do not start any type of supplementation without consulting with a physician.

Tyrosine hydroxylase is the key enzyme in the conversion of tyrosine to L-DOPA. It is contains iron which must be kept in the reduced (+2) state to function properly. Naturally, this means that the enzyme can be compromised if an iron deficiency is present. Recommended daily intake levels for iron can be found here.

It is believed that this tyrosine hydroxylase enzyme can be aided by maintaining ample levels of antioxidants such as vitamin C in the diet. Keeping antioxidant levels up to speed aids in maintaining this necessary form of the iron for the enzyme to function properly. In other words, the enzyme is intricately connected to antioxidant balances in the body. This is an often overlooked side-component of ADHD treatment via tyrosine supplementation. here is a link for the recommended daily intake for vitamin C.

Tyrosine hydroxylase is inhibited by its own products, the catecholamines (which include dopamine and norepinephrine, two of our later "targets" in the above diagrammed pathways). This means that we cannot expect to get high levels of dopamine in the brain by mega-supplementing with tyrosine, because this process shuts itself off.

Therefore, excessive tyrosine supplementation (beyond the level recommended by your physician) is essentially ineffective, and potentially harmful.

The main helper of the tyrosine hydroxylase enzyme, however, is the compound tetrahyrobiopterin. This is manufactured in the body, so supplementation for this is not necessary (except in the case of a few rarel genetic or metabolic disorders). Tetrahydrobiopterin and molecular oxygen (O2) supply the enzyme with the proper tools to convert the tyrosine to L-DOPA by chemically adding a hydroxyl (-OH) group, which can be seen in the diagrams near the top of the post.

Tetrahydrobiopterin synthesis is dependent on nutrient cofactors including zinc and magnesium. Recommended daily amounts can be found here for zinc and here for magnesium.

→ source (external link)

[zaratoo]

I found a blog article that summarizes tyrosine / tyrosine hydroxylase nicely in laymans language. 

 

Does Tyrosine Supplementation Actually Work for ADHD? (part 2)
Can ADHD symptoms be alleviated by supplementing with the amino acid tyrosine?
[...]
The main helper of the tyrosine hydroxylase enzyme, however, is the compound tetrahyrobiopterin. This is manufactured in the body, so supplementation for this is not necessary (except in the case of a few rarel genetic or metabolic disorders). [...]

→ source (external link)

AFAIK 5MTHF and D3 are essential for proper BH4 and TH metabolism. And neither of D3 deficiency (in those not supplementing) nor MTHFR mutation is rare at all. So one should consider them as the very first tier of support for this system. BH4 itself supplementation is rather questionable though.