There is no molecule I have ever taken that is a greater double-edged sword than MAO-B inhibitors. On the one hand, they are wonderful. On the other, they are awful.
Selegiline is an irreversible MAO-B inhibitor. MAO-B is the primary enzyme that breaks down dopamine and some trace amines. Selegiline was developed for the treatment of Parkinson’s disease. More recently, a transdermal patch (Emsam) was approved for the treatment of depression. Some people use selegiline as a cognitive enhancer because it elevates dopamine levels in a unique way.
Personal experience
A few years back, I went on a six-month-long journey around the world with one of my closest friends. As we were in India, I bought some selegiline because I had long been curious about its effects. I took 5mg at once.
On the first day I took it, my friend said something that annoyed me. Instead of talking about it like I normally would, I simply followed my impulses and snapped at him in a way that is quite unlike me. Back then, I did not think much of it. But in retrospect, this should have been an early warning sign.
A few days later, I attended a 10-day Vipassana meditation retreat where I had to meditate for approximately 14 hours a day. Despite being advised to discontinue the use of mind-altering substances, I continued taking a low dose of selegiline (1mg/d sublingually).
In some sense, meditation trains people to be less reactive. Tim Ferriss describes it as “You become response-able” meaning that one is able to actually make a response instead of an autonomic knee jerk.
On a neurobiological level, meditation trains people to suppress automatic urges & impulses and thereby increases the gap between stimulus and response. The cumulating effects of MAO-B inhibition, and consequently the progressive increase in dopamine levels, 100% did the opposite.
My gap between stimulus and response became progressively shorter. Instead of growing calmer, quieter, and more peaceful, I grew more impulsive, restless, and irritable. I had a hard-to-resist urge to be “productive”. Thanks to selegiline, my 10-day Vipassana meditation retreat was a complete waste of time.
My experience led me to believe that Buddhists are on a life-long quest to mind-train themselves to resist dopaminergic impulses, and that, speculatively, much of their training can be undone by an MAO-B inhibitor (which could in theory also be purposefully used to level up their training).
A couple of months later, I was working in a tedious sales job. I turned to my left-over selegiline stash. I combined low-dose selegiline with low doses of modafinil, which was potentiated by MAO-B inhibition. At first, it was fantastic. Clear head, motivation, no procrastination, assertiveness.
I was able to work long hours and did not need breaks. In fact, I did not even want breaks because selegiline made it impossible to just chill and be cool. Modafinil alone let me double my sales closed, but the addition of selegiline let me triple it. The company average was 2.2 sale closes per day. The company record was 14 closes per day. My daily average was 28. In three months of working, I made almost as much money as I now make as a doctor in a year.
Over time, I also started making riskier and more brazen sales. It’s possible, if not probable, that this was due to the impact the heightened levels of dopamine had on my willingness to take risks. While I won’t go into detail about what exactly happened, I ended up losing my job.
I was not surprised to learn that selegiline was the “limitless drug” employed by the fallen-from-grace crypto lord Sam Bankman-Fried, possibly contributing to his excessive risk-taking and eventually to his downfall.
Ever since money existed, there may have been a correlation between high dopaminergic activity and financial success. By using dopaminergic drugs, one may be able to “hack” this pharmacologically. However, this comes at the cost of increased risk-taking that could ultimately multiply everything by zero.
Because selegiline had undoubtedly increased my agency and motivation, I would turn to it one more time, this time at lower doses. Again, after a couple of weeks, I had the feeling of constantly needing “to do” something. I was impossible to chill.
I became more me-focused, and I got irritated easily when things did not go the way I wanted them to go. One day, I ended up yelling at my sister for almost no reason. I also started to argue more and more with my girlfriend and in the end, I lost her, which caused me a great deal of pain, suffering, and regret. In hindsight, I suspect that the selegiline played a non-minor role.
Selegiline increased my self-confidence, verbal fluency, mood, motivation, cognition, and agency. Uniquely, there was little to no tolerance. However, the upsides were not worth it. Selegiline killed my prudence and mindfulness and turned me into a person I did not want to be.
How it works
The science of MAO inhibitors is discussed in more detail in my article on moclobemide. In my experience, MAO-A inhibition (which increases primarily serotonin and noradrenaline and only to a lesser extent dopamine), makes me more present-oriented, while MAO-B inhibition (which increases primarily dopamine and trace amines), makes me more driven and future-oriented.
At low doses, selegiline is a selective and irreversible inhibitor of MAO-B, which increases storage levels of dopamine, so that more dopamine is released when a neuron fires.
Psychiatrist blogger Scott Alexander (the author of Slatestarcodex & Astral Codex Ten – two of my favorite blogs) summarized the effects of dopamine in a graph.
Dopamine is metabolized by both MAO-A and MAO-B (and some other enzymes). While MAO-B inhibition increases dopamine levels, high levels of MAO-A inhibition is thought to have an inverted-U-shaped curve effect on dopamine signaling (but possibly not dopamine levels).
At low levels of MAO-A inhibition, dopamine signaling increases, but at high levels of MAO-A inhibition dopamine signaling seems to decrease, presumably because high levels of serotonin act on midbrain dopamine neurons and decrease VTA-neuron firing.
If both enzymes are inhibited, dopamine levels increase more than from the inhibition of either enzyme alone. MAO inhibitors are discussed in more detail here.
Side effects from MAO-B inhibition include loss of impulse control, irritability, insomnia, an inability to chill, and weirdly, low blood pressure and tiredness. An increased risk for behavioral addictions has been reported in the literature, including pathological gambling, binge eating, and hypersexuality.
The bioavailability of selegiline is exceptionally low (10%) and somewhat unpredictable as the molecule is lipophilic and more readily absorbed with fatty foods. To circumvent this unpredictability, I always took it sublingually. However, taken sublingually, plasma levels increase by approximately five-fold, necessitating an appropriate decrease in dosage.
Sublingual administration also bypasses hepatic first-pass metabolism and therefore reduces the disproportionate inhibition of gastrointestinal and hepatic MAO-B, and reduces the formation of amphetamine-like byproducts, such as levo-methamphetamine.
To avoid the formation of amphetamine-like metabolites the cleaner MAO-B inhibitor rasagiline was developed. Rasagiline is a little more potent than selegiline (1mg of rasagiline = 10mg of selegiline if taken orally). At low doses, both are selective for MAO-B. At higher doses, their affinity for MAO-A increases non-linearly.
Even though the half-lives of selegiline and rasagiline are short, the duration of effects is awfully long. The MAO-B enzyme has a half-life of about 20-30 days, which means that a single dose will have an effect for about a month.
I discuss the science of MAO-inhibitors in more detail in my article on moclobemide, my most favorite antidepressant.
Interactions with other drugs
Compared to MAO-A inhibition, MAO-B inhibition is relatively benign in terms of pharmacodynamic interactions. However, inhibiting MAO-B potentiates the dopaminergic component of stimulants. For me, modafinil became twice as strong and a normal cup of coffee felt like two. At higher doses, selegiline loses its selectivity and starts to inhibit MAO-A as well.
MAO-A inhibition is far more dangerous and anything acting on monoaminergic systems will be potentiated. At the most extreme end, the combination with serotonergic drugs can lead to serotonin syndrome, the combination with noradrenergic drugs to a hypertensive crisis, and the combination with dopaminergic drugs to mania and psychosis.
MAO-B inhibition markedly increases the brain levels of endogenous phenylethylamine (PEA – aka “the body’s own amphetamine”) and other trace amines.
Interestingly, on selegiline, I got low-level addicted to dark chocolate. I even conditioned myself to prefer crappy-tasting 100% cocoa chocolate, probably because of the higher phenylethylamine (PEA) content. PEA functions as a catecholamine releaser. By itself, PEA has a low risk of addiction due to it being readily metabolized by MAO-B. However, if combined with an MAO-B inhibitor, it seems to be quite addictive.
I once read about a guy who took pure PEA in combination with selegiline for several months. Anecdotally, even years later he had not fully recovered (e.g., lethargy, apathy, anhedonia), possibly by having “fried” his dopaminergic system in a similar way to people taking high doses of amphetamines for prolonged periods of time.
What MAO-A inhibition vs. MAO-B inhibition feels like for me
The higher I go in moclobemide (a selective MAO-A inhibitor), the calmer, stiller, and more boring my mind becomes. Conversely, rasagiline (a MAO-B inhibitor) has the opposite effect on me. The higher I go, the more restless, driven, and more exciting my mind becomes. Whereas MAO-A inhibition makes me more present-oriented, content, and calm, MAO-B inhibition makes me more future-oriented, edgy, and impulsive.
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MAO-B inhibition may protect (somewhat) against the age-related loss of dopamine neurons.
The number of catecholamine neurons is highest at birth and begins a long, gradual downhill slide thereafter. Unfortunately, the dopamine-producing neurons are among the first neurons to degenerate, presumably due to oxidative and neurotoxic byproducts produced by the MAO-B metabolism of dopamine, resulting in Parkinson’s disease and eventually death.
When MAO-B is inhibited, dopamine is metabolized by other enzymes, such as MAO-A or COMT, which do not yield neurotoxic metabolites. Therefore, MAO-B inhibition is known to slow the decline of dopaminergic neurons even in non-Parkinson patients. I discuss this in more detail here.
The effects of selegiline on personally depend on the user’s age. Given that we lose about 7-10% of the dopaminergic neurons per decade, selegiline obviously has exponentially more powerful effects on younger people whereas people who are older folks are mostly “normalized”.
All “more dopamine” is not created equal.
Even though modafinil, a dopamine reuptake inhibitor, and selegiline, an MAO-B inhibitor, both elevate dopamine levels, they “feel” quite different. For example, for both me and some of my friends, modafinil increases focus and reduces task-switching, while selegiline has the opposite effect.
How come this difference if both elevate dopamine? The following is my personal hypothesis and has not been tested scientifically – or at least I am not aware of it having been tested. I believe that they feel different because of the different ways by which they elevate dopamine levels.
As a dopamine reuptake inhibitor (DATi), modafinil “locks” dopamine into the synaptic cleft. Consequently, on modafinil, the change in synaptic dopamine concentration between the action potentials of dopaminergic neurons is reduced and dopamine is always “flatly” elevated.
Conversely, as an MAO-b inhibitor, selegiline impairs dopamine metabolism, which leads to a greater-than-normal amount of dopamine being packaged into the soon-to-be-released vesicles, allowing for more dopamine to be released by a single action potential. Consequently, on selegiline, changes in synaptic dopamine concentration between action potentials are (presumably) increased.
Speculatively, it is because of this that selegiline does little for ADHD treatment – it may even make things worse. For example, it tends to make people more restless, hyperactive, and impulsive – core features of ADHD. However, to be fair, some people with ADHD claim that MAO-B inhibitors help them – whereas most claim that they make things worse. ADHD is discussed here: ADHD – To Treat Or Not To Treat?
Other experience reports
For a discussion of the molecular correlates of well-being, and links to accounts of various related molecules I have experimented with, read here.
For a full list of experience reports click here.
Sources & further information
- Opinion article: The Psychopharmacology Of The FTX Crash
- Scientific study: Transdermal selegiline for the treatment of major depressive disorder
- Opinion article: David Pearce – The Good Drug Guide
Disclaimer
The content available on this website is based on the author’s individual research, opinions, and personal experiences. It is intended solely for informational and entertainment purposes and does not constitute medical advice. The author does not endorse the use of supplements, pharmaceutical drugs, or hormones without the direct oversight of a qualified physician. People should never disregard professional medical advice or delay in seeking it because of something they have read on the internet.