Selegiline

Research summary.

[Disclaimer: Not medical advice. Purely a research article.]

Selegiline is a drug that's typically used to treat parkinson's and sometimes certain kinds of depression.

It works by irreversibly inhibiting monoamine oxidase B (MAO-B) which is the enzyme that metabolizes dopamine. In other words, it destroys the enzyme that destroys dopamine.

Of course, dopamine still gets metabolized, but slower and using different — better — enzymes.

See, the issue with dopamine is that it's primarily metabolized by MAO-B. The resulting metabolites are significantly neurotoxic, as they are reactive oxygen species (ROS).

When MAO-B is inhibited, dopamine is metabolized using enzymes like diamine oxidase, which results in non-neurotoxic metabolites.

The "irreversible" part of "irreversible inhibitor" is important. Enzyme inhibitors are typically reversible, which means that they just occupy the enzyme resulting in the substrate (the substance that would be metabolized by this enzyme) not being able to bind, or at least not in high quantities. The inhibitor competes with the substrate for the enzyme.

Irreversible inhibitors, on the other hand, destroy the enzyme. The effect is much longer lasting. Irreversible sounds permanent, but it's irreversible in the sense that it does something that can't be reversed (destroys the enzyme), rather than irreversible in the sense that the body can never go back.

The body naturally gets rid of & synthesizes new enzymes, so in some time, the MAO-B would replenish if you halted use. It's said to take around 45 days for the inhibition to halve, then another 45 days for the remaining half to halve, etc.

Why?

1. Zero risk of Parkinson's disease
2. Extremely low risk of Alzheimer's disease
3. More focus, motivation, and better mood
4. Less anxiety
5. Longer lifespan

Here are two excerpts from my notes:

• Extremely mindful and present focus today on 5mg selegiline (last 2 days 10mg, today 5mg, I'm probably fully inhibited by now). Focused on coding so well. Literally did more work today than in past few weeks.
• Ever since I'm on selegiline, I find it easy to get into flow and actually do a lot of work. It also makes modafinil less euphoric and more focused. Overall the feeling is present mindfulness.
  • Sounds almost too good, yet it's so subtle. I don't think placebo would be doing this.

If that sounds appealing, read on. I'll discuss each of those things in detail in the following paragraphs.

Monoamine oxidase

Monoamine oxidase has two subtypes. Monoamine oxidase A and monoamine oxidase B.

A is used to metabolize things like serotonin, and — importantly — tyramine.

B is used to metabolize dopamine, phenethylamine (PEA), amphetamines (Adderall, Vyvanse, methamphetamine)

MAO-A can safely metabolize a lot of the things that MAO-B can metabolize, but not vice versa. MAO-B's products are a lot more vile.

The issue with MAOIs

Monoamine oxidase inhibitors (MAOIs) are often considered dangerous — especially if they're irreversible — due to possible interactions with some compounds that are very widespread.

As mentioned above, MAO-A metabolizes tyramine. This is a very widespread substance, found in infamously in cheese. If you were MAO-A inhibited and you ate a lot of — especially aged — cheese, you'd get hypertensive crisis which is a very real medical emergency with the potential of ending in death.

People sometimes think that this happens with MAO-B inhibition as well, and for that reason they treat selegiline as something dangerous.

However, this notion is not correct. MAO-A inhibition (typically used for depression treatment) is indeed a problem, but MAO-B inhibition poses practically zero issues.

The only notable interaction that selegiline has is phenethylamine (PEA) and its derivatives (amphetamines and possibly some other stimulants). They can become more potent and longer lasting.

This is especially true with PEA. PEA is sold over-the-counter as a dietary supplement in many countries (in fitness stores and such), but if you took a high enough dose, it would feel like MDMA or similar euphoric amphetamines. PEA is generally legal because abusing it is very impractical, the high lasts only a few minutes, and it comes with side effects such as extreme blood pressure.

However, when you mix PEA with MAO-B inhibitors, it becomes much longer lasting, and much more potent. Aside from the high blood pressure which persists, it's an extremely recreational combination, many people citing it as better than cocaine.

In other words, don't take PEA (unless you want ^ that) when MAO-B inhibited (and don't take it normally anyway, it's an overmarketed, shitty supplement that has no fitness benefits or anything like that).

Some natural things can be somewhat high in PEA, for example cocoa. But you would have to eat an unimaginable amount of pure cocoa to have any real issues, so that's not a problem.

So, in short: for all intents and purposes, MAO-B inhibition has zero negative interactions for regular people.

Only if you're taking amphetamines (e.g. for ADHD) know that they might last longer and be more potent. This interaction is typically not dangerous, but it's just important to know it. Selegiline can likely reduce the vast majority of MDMA's neurotoxicity, but it will make it stronger, so even if it's making it less toxic, it could make it — if unexpected — more dangerous because of the higher potency. Anyway, you get it.

Selegiline metabolites

Oral selegiline has (a small amount of) amphetamine metabolites, namely levoamphetamine and levomethamphetamine (the left enatiomers of amphetamine & methamphetamine).

Did you know that l-methamphetamine — which, again, is methamphetamine but just the left-oriented variant — is sold OTC as a nasal spray? You didn't, now you do. It doesn't have as strong central (brain) effects as d-methamphetamine (the right-oriented variant), and it has stronger peripheral (body) effects, so it's a good decongestant.

The metabolites are quite negligible, but they can be almost completely prevented by taking selegiline buccally, as explained in the next section.

Also, selegiline in itself acts a bit like an amphetamine (it's a dopamine reuptake inhibitor/possibly slight releasing agent), so don't take it late in the day, it can disrupt sleep.

Use

In clinical settings, selegiline is typically used orally in 5-10mg doses per day.

This works, but it's suboptimal.

MAO is present all over the body, and you really only care about the brain. Also, being MAO inhibited in the peripheral nervous system is infinitely more dangerous (but stil almost completely safe), because if you're MAO inhibited just in the brain, eating a lot of PEA won't have as big of an effect as if you were inhibited in both places. The peripheral MAO will still take care of it.

So, the better option is to take it buccally. This has two benefits (study):

1. It's about 8x more efficient
2. It's more selective for brain MAO-B
3. It bypassess first-pass metabolism which means much less amphetamine metabolites

And how much to take? When you're fully inhibited, you want to take 1.25mg buccally to remain fully inhibited. To reach full inhibition, you probably need to consume 10-15mg buccally total (remember that the inhibition stacks, since it's very slow to reverse, so you can just do this over the course of multiple days).

It's also worth noting that selegiline will start slightly inhibiting MAO-A at high doses. So when reaching full inhibition, rather take less for multiple days than a massive dose on one day, even if that would be effective for MAO-B inhibition.

Is it safe?

There have been studies examining mice whose MAO-B has been completely removed genetically. They showed zero undesirable effects. They lived longer and were less fearful. The only observable bodily effect was an increased amount of PEA in urine, but ... does that matter.

Transgenic mice that are unable to produce MAO-B are shown to be resistant to a mouse model of Parkinson's disease

In addition, they exhibit behavioral disinhibition and reduced anxiety-like behaviors

Inhibition of MAO-B in rats has been shown to prevent many age-related biological changes such as optic nerve degeneration, and extend average lifespan by up to 39%

While people lacking the gene for MAO-A display mental retardation and behavioral abnormalities, people lacking the gene for MAO-B display no abnormalities except elevated phenethylamine levels in urine, raising the question of whether MAO-B is actually a necessary enzyme

The prophylactic use of MAO-B inhibitors to slow natural human aging in otherwise healthy individuals has been proposed, but remains a highly controversial topic

Yeah, this is a controversial article 😉

The normal activity of MAO-B creates reactive oxygen species, which directly damage cells.[13] MAO-B levels have been found to increase with age, suggesting a role in natural age related cognitive decline and the increased likelihood of developing neurological diseases later in life.[14] More active polymorphisms of the MAO-B gene have been linked to negative emotionality, and suspected as an underlying factor in depression.[15] Activity of MAO-B has also been shown to play a role in stress-induced cardiac damage.[16][17] Over-expression and increased levels of MAO-B in the brain have also been linked to the accumulation of amyloid β-peptides (Aβ), through mechanisms of the amyloid precursor protein secretase, γ-secretase, responsible for the development of plaques, observed in Alzheimer's and Parkinson's patients. Evidence suggests that siRNA silencing of MAO-B, or inhibition of MAO-B through MAOI-B (Selegline, Rasagiline), slows the progression, improves and reverses the symptoms, associated with Alzheimer's disease and Parkinson's disease, including the reduction of Aβ plaques in the brain

If MAOB is inhibited, then more DA is available for proper neuronal function, especially in Parkinson's Disease

Where to get it

This is tough. In most countries, it's a prescription-only medicine. Sometimes asking a doctor for it will work, other times knowing ... people will work, and other times ordering it from other countries will work. Can't say much more.

Research

Selegiline is a great antioxidant

Selegiline: a molecule with innovative potential

Selegiline showed antioxidant activity and reduced the fat accumulation in the liver of rats on lipid-rich diet

Selegiline and lymphocyte superoxide dismutase activities in Parkinson's disease

Significant excesses of both SOD forms were found among PD cases compared with controls; however, the excesses were found exclusively among PD patients treated with the monoamine oxidase inhibitor selegiline

The antioxidant effects are interestingly compounding.

When less reactive oxygen species are created by dopamine metabolism,

Effect of low-dose treatment with selegiline on dopamine transporter (DAT) expression and amphetamine-induced dopamine release in vivo

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

Striatal levels of DAT were elevated after 1 and 21 days treatment with selegiline

More DAT means increased function of dopaminergic stimulants, again a good thing, if DAT were decreasing that would mean tolerance similar to that of prolonged stimulant (e.g. methylphenidate) use. But we're seeing the opposite.

Online reports

Positive reports

Overall, selegiline generally makes me feel way more on top of things, and in more ways than one. I'm able to "just do it," now. Don't have to give myself mental pep talks nearly as often to get things done. Chores are a fucking breeze. Motivation just isn't much of an issue at all. My mind is much clearer and snappier while on it; conversation flows much quicker and easier. It's fairly improved my working memory; like I said, I'm able to multitask better, and I can switch trains of thought much more fluidly. My to-do lists are no longer daunting symbols of hard work and responsibility.. now, I'm usually able to make short work of a day's worth of tasks, AND I'll have free time for my personal projects and pursuits afterwords.

I haven't seen that big of an effect, but I already take dopaminergic stimulants — modafinil, or phenidates — on a daily basis. They're neuroprotective, improve cognition, focus, and mood. It would be a terrible choice not to improve your life in all ways when you can easily do it.

That said, I still do feel selegiline. I'd say that it's effects are on the same level as magnesium — it's very much a background thing, you don't get like a rush of effects (because it's so long lasting). It also makes me much more present and calm. Really feels like the result of a mindfulness practice.

And it's sustainable for years:

The positives seem to far outweight the negatives at this time. So far so good. I have researched a lot about Selegiline and found reports of people that took it every day for years with no ill effects

Many drugs eventually lead to tolerance, but selegiline seems to be mostly exempt from this. Without selegiline, you'd be losing dopaminergic neurons (or rather, axons — dopaminergic oxidative stress causes damage to axon terminals). So that's one way you end up with more dopaminergic activity. Another is that enzyme inhibitors generally have less tolerance than receptor agonists, and the dopaminergic system is pretty forgiving in this respect anyway. And selegiline increasing DAT expression, DA efficiency, PEA efficiency, and more just leads to a sustainably better dopaminergic signaling.

Even if you developed complete tolerance, you'd still not have MAO-B, which would mean (at the very least):

1. Being immune to Parkinsons
2. Higher level of antioxidants in the body
3. More dopamine neurons/axons

So even if all of the immediate subjective effects (or cognitive benefits) went away, you'd still be much better off.

Negative reports

These typically list:

• Agitation, but usually only at high daily doses
  • Doesn't personally happen to me, I use low doses sublingually, so it may be the metabolites
• General side effects of stimulants, though much much milder

I imagine a small number of people can be sensitive enough to selegiline that the side effects would outweigh the benefits, but this would be extremely rare. Likely people who are sensitive to all stimulants.

I tried to do my best to outline all the associated risks, because it's never a good idea to recommend substances without properly mentioning all negatives.

That said, this is a very safe substance.

Closing

Selegiline is an extremely promising drug (more of a supplement actually) that's been known for years, but only recently started to gain popularity for life enhancing purposes. This is partially due to the fear of MAOIs, but as explained above, that's a complete non-issue with selective MAO-Bs such as selegiline. It's a safe way to get a lot of benefits.

It seems that MAO-B is a useless enzyme at this point. We still don't know why it existed, but it may have made sense back when our diets were different and bodies were smaller. The body adapted to external dangers (tyramine — MAO-A, PEA — MAO-B), but these parts of the nervous system are very very old. You may ask why didn't the body get rid of MAO-B, and the answer is likely that living > 60 years was never a priority, being in a high state of fear decreases life quality but increases increased survival, and that's the state our bodies are stuck in. Evolution is very slow and human progress got extremely fast.

So just like many other things — high anxiety, social pressure, ... — dopamine metabolism over the course of 60+ years is something our bodies didn't yet adapt to.

Naturalistic solutions win over modern solutions in 9/10 cases, but there is a place and time for medicines and supplements, and this is one of them. Our ancestors had herbal medicine that we have largely forgotten and are now rediscovering through pharmacological science. We have drugs to treat illnesses which would have been deadly 100 years ago.

Those things help with survival. And the next step after keeping your life is: having a good life.