37 replies to this topic

[Galaxyshock]

Nice findings. Selegiline, you sexy beast, starting to feel more and more tempting.

 

What is the consensus on its amphetamine-metabolites, are they relevant when taking Selegiline in low-doses?

[gamesguru]

https://en.wikipedia...methamphetamine

 

Apparently the enantiomeric effects are very dividing with amphetamine. The D-enantiomer has the predominant stimulant effects, whereas the L-enantiomer is much milder (and less rewarding).

 

I had to fact check a redditor, but (see wiki article) the L-enantiomer of methamphetamine is actually found in OTC products, such as nasal decongestants.

 

Since most selegiline is L-deprenyl, it wouldn't have much effect.

 

Even dosing D-deprenyl would only likely matter at large doses. I was using L-deprenyl in very small amounts. First week I used 5 mg (1.25 mg every other day). Then I took a week off before going through only 3.75 mg the next week.

 

The buccal or sublingual route of administration bypasses 95-98% of the liver metabolism. For a 500 mcg sublingual dose, scarcely enough amphetamine metabolites would be generated to affect a fruit fly. But you can see in the sci-hub study on the previous page, selegiline has a short half life compared to the amphetamine metabolites, so with the oral route they do build up to an extent and have a larger "area under curve" than selegiline itself.

 

My own belief is that the amphetamine metabolites have no measurable impact (good or bad) on micro-dose treatment, and that at the given level of exposure no negatives effects are known.

[gamesguru]

I wonder if this can also be avoided by lower doses of an irreversible inhibitor? Curiously, I am deficient in the DAO enzyme since early adulthood (but this is peripheral, I'm not sure about the CNS).

 

Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer’s disease
https://www.science..../sciadv.aav0316

Monoamine oxidase–B (MAO-B) has recently emerged as a potential therapeutic target for Alzheimer’s disease (AD) because of its association with aberrant γ-aminobutyric acid (GABA) production in reactive astrocytes. Although short-term treatment with irreversible MAO-B inhibitors, such as selegiline, improves cognitive deficits in AD patients, long-term treatments have shown disappointing results. We show that prolonged treatment with selegiline fails to reduce aberrant astrocytic GABA levels and rescue memory impairment in APP/PS1 mice, an animal model of AD, because of increased activity in compensatory genes for a GABA-synthesizing enzyme, diamine oxidase (DAO). We have developed a potent, highly selective, and reversible MAO-B inhibitor, KDS2010 (IC50 = 7.6 nM; 12,500-fold selectivity over MAO-A), which overcomes the disadvantages of the irreversible MAO-B inhibitor. Long-term treatment with KDS2010 does not induce compensatory mechanisms, thereby significantly attenuating increased astrocytic GABA levels and astrogliosis, enhancing synaptic transmission, and rescuing learning and memory impairments in APP/PS1 mice.

 

[gamesguru]

I found a couple of curious studies from 2023. However, the concentrations used in the studies are far below the levels used for life extension or even for antidepressant purposes; it's not clear that the differentiation of stem cells into neurons plays a significant role in the clinical effect seen in humans, but it's interesting to contemplate and consider — among the growing body of positive research on this compound — the possibility that these mechanisms play a role.

 

Synergistic Effect of Lovastatin and Selegiline on the Differentiation of Bone Marrow Stromal Cells Into Neuron-Like Cells | Jentashapir Journal of Cellular and Molecular Biology | Full Text

https://brieflands.c...es/jjcmb-141092

 

Selegiline induced differentiation of rat bone marrow mesenchymal stem cells to dopaminergic neurons in vitro

https://pharmacia.pe...article/107909/

 

And here are a few more studies — once again, all from 2023 or later.

 

Effect of selegiline as a monomine oxidase B inhibitor on the expression of neurotrophin mRNA levels in a contusion rat model of spinal cord injury: Neurological Research: Vol 45, No 3

https://www.tandfonl...12.2022.2129761

"The results showed that administration of selegiline improves locomotor function and increases mRNA levels of BDNF, GDNF, NT-3, and NT-4."

 

Neuroprotective Effects of Selegiline Agent Methamphetamine-Prompted Mood-Related Behavior Disorder : International Journal of Preventive Medicine

https://journals.lww...e_agent.78.aspx

 

Selegiline ameliorated dyslipidemia and hepatic steatosis in high-fat diet mice - ScienceDirect

https://www.scienced...567576923002217

 

Pharmaceutics | Free Full-Text | Selegiline Modulates Lipid Metabolism by Activating AMPK Pathways of Epididymal White Adipose Tissues in HFD-Fed Obese Mice

https://www.mdpi.com...4923/15/11/2539

 

MAO – B Inhibitor “Selegiline” Attenuates Oxidative Stress and Arthritic Parameters in an Invitro Repurposed Studies | Journal of Biomedical Engineering

https://swyxgcx.com/...article/view/17

 

[High-IQ-Toilet]

The prominent challenge for selegiline is undoubtedly a titrated dosage and proper ROA, which should ideally be administrated transdermally via EMSAM-patches. EMSAM dosages are available by 6mg, 9mg, or 12mg: the highest EMSAM dosage significantly inhibits MAO-A activities, resulting in noticeable anxiolytic effects. Selegiline's amphetamine metabolites, as current clinical research suggests, do not exhibit deleterious cognitive effects as EMSAM's dopaminergic-enhancing activities are much more heavily TAAR1 transporter-dependent. 

[gamesguru]

The prominent challenge for selegiline is undoubtedly a titrated dosage and proper ROA, which should ideally be administrated transdermally via EMSAM-patches. EMSAM dosages are available by 6mg, 9mg, or 12mg: the highest EMSAM dosage significantly inhibits MAO-A activities, resulting in noticeable anxiolytic effects. Selegiline's amphetamine metabolites, as current clinical research suggests, do not exhibit deleterious cognitive effects as EMSAM's dopaminergic-enhancing activities are much more heavily TAAR1 transporter-dependent. 

 

Continuous delivery has intriguing effects. The closest I came to that was a 5-7 day stretch where I had titrated up to 5-6 mg sublingually throughout the day. It had a powerfully stimulating and mood-lifting effect. But I also started getting food interactions and the "pressor response."

 

Is there any evidence the side effects are worse at this level? More issues with insomnia, impulse control, or high blood pressure?

 

Ultimately, I like the lower dose. Taking 1 mg a few days a week gives a good boost while staying in the honeymoon phase. I don't think Selegiline is the most putative antidepressant, nor that the larger doses needed for an anxiolytic effect are the healthiest. I enjoy it in the low-end regime, where it serves as a mild longevity agent and stimulant.

 

The TAAR1 mechanism[1] is a new understanding of an old phenomenon, often called CAE or "catecholamine activity enhancer." I think it is somewhat dose-dependent (more powerful at larger doses).

 

 

References

 

[1] (PDF) Striking Neurochemical and Behavioral Differences in the Mode of Action of Selegiline and Rasagiline

https://www.research..._and_Rasagiline

[High-IQ-Toilet]

Well, is selegiline the solo medication that you are using? Personally, I have rarely used EMSAM in isolation as one should take advantage of the catecholamine enhancement if they already committed to the MAO-B inhibition. Sublingual ROA for selegiline HCL was far inferior compared to even baseline transdermal EMSAM in my experiences, as buccal absorption miss out on many of the selegiline's true benefits, while simultaneously maintaining negative side effects of oral selegiline not found in EMSAM.

 

Moreover, the myth of rasagiline as the "upgraded" selegiline is unfortunately too often perpetuated: as demonstrated in this 2023 research, rasagiline lacks the dopaminergic-enhancing procognitive effects of selegiline, consequently rendering rasagiline as an unsuitable Anti-Parkinsonian treatment— "[moreover] as rasagiline does not exhibit a CAE effect, in contrast to selegiline, this might explain why '…based on current evidence, rasagiline cannot be said to definitely have a disease-modifying effect'"—unlike selegiline, which in combination with L-DOPA, reflects nontrivial efficacy in ameliorating symptomatic cognitive deficients for Parkinson's patients.

 

Theoretically, one can replenish the vesicular TAAR1/2 transporters with a tyrosine hydroxylase upregulator like bromantane.

 

Striking Neurochemical and Behavioral Differences in the Mode of Action of Selegiline and Rasagiline
Int. J. Mol. Sci. 2023, 24(17), 13334; https://doi.org/10.3390/ijms241713334

→ source (external link)

Edited by High-IQ-Toilet, 14 April 2024 - 07:13 PM.

[gamesguru]

What are the negatives, just gut inhibition/tyramine effect? Why would sublingual be any different than transdermal? You can spit it out to avoid gut interaction. But at a low dose, I don't even bother.

 

Rasagiline does act as a neuroprotectant in the MPP model of toxicity. While Rasagiline may not as profoundly inhibit MAO-A or have as many case reports behind it, we should not discount it entirely. I haven't tried Rasagaline. But I have read promising studies and seen anecdotal evidence.

 

I would like if Selegiline were more effective, or if it were the only medicine I needed, yes. What dose do you think the CAE effects begin/end at?

 

I'm unsure if a Tyrosine Hydroxylase activator would suffice, as long-term Selegiline treatment features DAO-enzyme upregulation and other compensatory mechanisms.  Taking appropriate tolerance breaks is likely the optimal solution to stay in the honeymoon phase.

 

Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer's disease - PMC

https://www.ncbi.nlm...#sec-a.j.btitle