[Epistemic status: MAOIs probably are the most powerful antidepressants – more evidence for this can be found in an excellent recent post on SlateStarCodex.]

I’ve recently read the absolutely excellent classic “The Good Drug Guide” by David Pearce.

Pearce is a hardcore transhumanist whose ultimate goal is to abolish all suffering. Even better, he’s not shying away from pratical, maybe drastic interventions in the here and now. Gene therapy, nanotechnology, FAI, eugenics all sound pretty exciting but they are still a long way off. So what can we do now? Let’s hear David Pearce:

There’s clearly a strong causal link between the raw biological capacity to experience happiness and the extent to which one’s life is felt to be worthwhile. High-minded philosophy treatises should complicate but not confuse the primacy of the pleasure-pain axis. So one very practical method of life-enrichment consists in chemically engineering happier brains for all in the here-and-now. Yet how can this best be done? Any strategy which doesn’t subvert our inbuilt hedonic treadmill of inhibitory feedback mechanisms in the CNS will fail. Political and socio-economic reforms offer at best a lame stopgap. To the scientific naturalist, all routes to happiness must ultimately be biological – “culture” and “talk-therapy” alike must be neurochemically encoded to exert any effect on the psyche. Some of these routes to happiness involve the traditional environmental detours. They are too technical, diverse and futile to tackle here. If the quality of our lives is to be significantly enhanced in the long term, then the genetically predisposed set-point of our emotional thermostats needs to be recalibrated. The malaise-ridden norm typically adaptive in humanity’s ancestral environment must be scrapped. So while we wait until germ-line gene-therapy to promote mental super-health can become standard, it’s worth considering instead how ordinary early 21st Century Homo sapiens can sustainably maximise emotional well-being with only present-day pharmacology to rely on. No less importantly, how is it possible to combine staying continuously “better than well” with retaining one’s sense of social and ethical responsibility to other people and life-forms?

So, naturally, drugs are the answer. To summarize: Since most of life is either pretty shitty or boring – at least if you really think about it – and even worse, evolution programmed us to feel shitty and discontent it’s a moral obligation to take drugs if you want to abolish suffering. I like this line of reasoning.

Pearce describes but ultimately dismisses almost all available classes of legal and illegal drugs as not very useful (such as the amphetamines, cocaine, opioids like heroin or morphine, GHB, psychedelics, MDMA and the more medical drugs like SSRIs, tricyclics, benzodiazepines and various other ones). I don’t have any personal experiences here (of course!), but from what I’ve heard I have to agree with him. Taking psychedelics or maybe MDMA a few times a year can enrich your life and help you to see the world with fresh eyes, but even they are not a panacea – not by a long shot.

Further in the text, he mentions some antidepressants and cognitive enhancers that seem somewhat promising, at least for some purposes. E.g. amineptine (unfortunately discontinued cause it was “addictive”), oxytocin (still pretty new), dopaminergic substances like pramipexole or ropinirole, bupropion (good stuff), tianeptine (serotonin reuptake enhancer and neuroprotective), St. John’s worth (SSRI and maybe a MAOI with little side effects) and lastly modafinil (also good stuff), to name a few.

Alas, none of them are truly amazing. But there’s light at the end of the tunnel. Lastly, Pearce discusses the MAOIs, short for monoamine oxidase inhibitors. MAO comes in two classes, MAO-A and MAO-B. MAO-A primarily breaks down noradrenaline and serotonin and to a lesser degree dopamine, MAO-B mainly dopamine. If you take MAOIs they will destroy those evil MAO-guys thereby indirectly increasing your levels of those nice neurotransmitters significantly. Sounds good? IT IS!

The first MAO was accidentally discovered as a treatment for tuberculosis. But not only tuberculosis was cured. Those patients were described “as dancing in the halls” and “inappropriately happy”.

Now, there are some serious side effects to MAOIs. If you combine them with other serotonergic substances like e.g. SSRIs, MDMA or some psychedelics you’re risking a possibly lethal serotonin syndrome. Taking other noradrenargic substances could cause a fatal hypertensive crisis. And in combination with MAOIs dopaminergic substances could lead to psychosis. Aslo eating tyramine-containing food is pretty dangerous. Basically, you will be very sensitive to all drugs and foods that increase your neurotransmitters. Normally, there are enough MAOs in your body to break down excess amounts of neurotransmitters, but since you’re taking MAOIs that isn’t the case anymore. Some of you may say “Perfect, now I can reduce my dosages and will spend less money on drugs”. I don’t know, maybe you’re even right. It would be interesting to know if taking e.g. MDMA just definitely leads to a serotonin syndrome or if you just need e.g. 1/10 of your normal dosage. Personal experiments would be enlightening but also pretty dangerous.

Anyhow, not eating chocolate, cheese, bananas and myriads of other foods and watching your diet like an obsessive-compulsive freak is probably not trivial for some people. On the other hand, feeling super-euphoric all the time sounds also quite nice, doesn’t it?

So, what are some MAOIs? At first there is moclobemide. It’s among the newest ones and also the least dangerous since it’s specifically inhibits only MAO-A, and not MAO-B (or to a significantly lesser degree; something like 80% to 30% or so). Also, it’s a reversible MAO inhibitor. Irreversible MAO-inhibitors destroy MAO for good. It takes about 2-3 weeks for your body to rebuild them. If you’re taking moclobemide however your MAO-levels will be back to normal after 1-2 days or so. On low to moderate doses you don’t have to watch your diet. Snorting too many lines of amphetamines could still lead to an untimely and painful death. I don’t know if it’s compatible with bupropion, modafinil or some mild cognitive enhancers like that. (I would like to say that I don’t want to find that out, but actually I do. I’m thinking about using super-small amounts and slowly increasing the dosage. Now I also see that drug prohibition makes sense. Maniacs like me, who gamble with their life have to be protected from themselves.)

So moclobemide is almost safe. But also kinda boring, at least in comparison to the following drug. I’m too lazy to write, so I’ll just quote David Pearce:

SELEGILINE (l-deprenyl, ELDEPRYL, EMSAM)

A recent New York study showed that smokers had on average 40% less of the enzyme, monoamine oxidase type-B, in their brains than non-smokers. Levels returned to normal on their giving up smoking. Not merely is the extra dopamine in the synapses rewarding. The level of MAO-b inhibition smokers enjoy apparently contributes to their reduced incidence of Parkinson’s and Alzheimer’s disease. Unfortunately they are liable to die horribly and prematurely of other diseases first. One option which the dopamine-craving nicotine addict might wish to explore is switching to the (relatively) selective MAO-b inhibitor selegiline, better known as l-deprenyl. Normally the brain’s irreplaceable complement of 30-40 thousand odd dopaminergic cells tends to die off at around 13% per decade in adult life. Their death diminishes the quality and intensity of experience. It also saps what in more ontologically innocent times might have been called one’s life-force. Eighty percent loss of dopamine neurons results in Parkinson’s disease, often prefigured by depression. In future, the mood-enhancing transplantation of customized stem cells may restore a youthful zest for life in dopamine-depleted oldsters: such stem cell-derived monoaminergic grafts are currently on offer only to depressed rodents. Deprenyl has an anti-oxidant, immune-system-boosting and dopamine-cell-sparing effect. Its use boosts levels of tyrosine hydroxylase, growth hormone, superoxide dismutase and the production of key interleukins. Deprenyl offers protection against DNA damage and oxidative stress by hydroxyl and peroxyl radical trapping; and against excitotoxic damage from glutamate. Whatever the full explanation, deprenyl-driven MAOI-users, unlike cigarette smokers, are likely to be around to enjoy its distinctive benefits for a long time to come, possibly longer than their drug-naïve contemporaries. For in low doses, deprenyl enhances life-expectancy, of rats at least, by 20% and more. It enhances drive, libido and motivation; sharpens cognitive performance both subjectively and on a range of objective tests; serves as a useful adjunct in the palliative treatment of Alzheimer’s and Parkinson’s disease; and makes you feel good too. It is used successfully to treat canine cognitive dysfunction syndrome (CDS) in dogs. At dosages of around 10 mg or below daily, deprenyl retains its selectivity for the type-B MAO iso-enzyme. At MAO-B-selective dosages, deprenyl doesn’t provoke the “cheese-effect”; tyramine is also broken down by MAO type-A. Deprenyl isn’t addictive, which probably reflects its different delivery-mechanism and delayed reward compared to inhaled tobacco smoke. In November 2004, Yale University researchers launched a study of deprenyl for smokers who want to quit tobacco. Whether the Government would welcome the billions of pounds of lost revenue and a swollen population of energetic non-taxpayers that a switch in people’s MAOI habits might entail is unclear.

Now we’re entering truly exciting territory. It also explains why quitting smoking often results in (mild) depressive symptoms. Here are more reports from Erowid:

I am a 52 y. o. male who has experimented w/ many drugs both legal and illegal. For the last several years my experimenting has been limited to legal drugs. Deprenyl is very impressive. I’ve just finished using my first 300mg bottle (12 ml )of Selegiline solution which has lasted several months. The effects are always consistent beginning about 20 minutes after I place 3-6 drops under my tongue. I definitely have a heightened sense of well-being and enhanced energy levels. Sometimes 6 drops is a bit too much and I feel somewhat buzzed. It is a good all purpose pick me up that never has interfered w/ sleep or apetite. Women look SOOO MUCH better. And when it comes to sex it reminds me somewhat of cocaine w/o any of the bad side effects. It is awesome to feel so ‘possessed’ AND empowered, focussed and in full capacity to enjoy. My male friends have basically the same opinion. I wonder how can something so good be so little known. Women seem to have similiar experiences EXCEPT it doesn’t seem to do much for their libido.

Um, yeah. I have to try this stuff. But there are more:

I’ll be 60 years old next month and have been using Deprenyl for about the past 10 years. In most respects it’s difficult to quantify the effects of this compound: in terms of its reputed anti-aging benefits I can say that I am very active, never get sick and am still alive. As a cognition enhancer it leaves me fairly unimpressed; my short-term memory isn’t nearly what it once was and I seem to suffer the same CRS (Can’t Remember Shit) syndrome as most or all of my peers. …. Apart from this, I have noticed that Deprenyl in the doses I use is a fairly good mood enhancer and is completely without any undesireable side-effects. Of the many interesting plants and pharmaceuticals I’ve experienced over the past 40 years, this seems to be one of the most unequivocally helpful and benign.

Here’s another one:

First off, I’m a 19 year old male, about 170lbs, who is experimenting with nootropics out of curiosity. A few months ago, I ordered a bottle with 60 doses of 5mg Selegiline from a research chemical site and took it pretty much every day. The day I started taking it I noticed a marked increase in motivation. For me it was money; there was a huge desire for me to make as much money as possible. I had never been a material person at all, and although I had money, I never thought about doing anything with it other than spending it. I guess some might say that being possessed by money is a bad thing, but the feeling was/is nothing short of complete empowerment. I loved doing math problems in my head involving money; the thinking was so clear. I went from having a bit under 500 dollars in the bank to over $10,000 in the two months that I had taken it. Of course I can’t quite disclose how I made this money, but I have to say that I engaged in activities that I probably wouldn’t have without Selegiline. Of course that isn’t the only feeling I noticed on Selegiline. I was motivated to use better vocabulary while speaking to people. I used to be pretty goofy and not many people really took me seriously. Now, when I talk, I feel that people listen. There is a noticable increase in the strength of my voice. I would say that I probably had low self confidence before taking Selegiline, now when I word things it is not in the ‘may I’ form, it’s ‘I will’. It makes me tend to look down on most people, but not in such a way that it would affect friendships, although a few friends mentioned to me that I had changed because of my general mindset. This probably sounds incredibly cocky, but it’s true confidence. I’m still nice to people, it’s just that they now seem to look up to me. Another benefit is the emotional ‘numbing.’ Before Selegiline I would jump at any chance with a decent looking girl and become attached pretty quickly in a flurry of emotions. On it, my thinking is completely rational and emotions never affect my thinking. I’m not even looking for a girlfriend until one can rationally show me that she is really worthy. Girls love to play the game, to say the least. I’m calmer, without emotional outbursts. When I get upset with people, I simply use my ‘enhanced’ charisma to undermine them, rather than losing control. As far as in combination with drugs; when I smoke weed I don’t feel as high; or at least, my speech and thinking are not as detrimented. With cocaine, the feeling of euphoria is minimized, which is not a terribly bad thing. It’s almost like most of the euphoria associated with cocaine is already there before I snort it. I know Selegiline isn’t considered an upper, but it feels like one in this sense. I am also definitely more talkative on it, although this may be a result of the increased confidence. After being off of it for a week and a half, I started to have those uncontrollable feelings for girls again. I also lost the ability to socialize effectively and the field of eligibles began to shrink. After about a month, I decided to hop on the train again and order another bottle. I try not to make judgements based on placebo effects. I was pretty skeptical of it when I first tried it, as most nootropics tend to be pretty subtle. However, after a few days I realized that this is the closest I can get to a stimulant without the negative effects. It’s definitely not placebo, and I can say that it makes more of a difference than all of the other nootropic I have tried combined.

I hear you. Placebo effect, selection effects and what not. Anyways, I read many experience reports on SSRIs and other ADs, but the ones on selegiline are the most promising. Only side effect is insomnia which is a bummer, but there are no free lunches I guess.

If this isn’t enough, here is our beloved Wedrifid from LessWrong (who also takes this stuff regurarly, if I remember correctly):

Just elaborating here on interactions with selegiline (which is a drug I highly recommend, by the way). The active ingredient in chocolate that interacts with the MOAI in selegiline is phenylalanine. The same amino acid discussed earlier that serves as a precursor to dopamine, norepinephrine and adrenaline. It’s what people refer to when they talk about chocolate’s “happy hormone”. Normally phenylalanine is fairly mild. Take a whole bunch and you may notice a boost in mood – particularly if stress has depleted your reserves. Even then it doesn’t last long. But with selegiline in the system it is a whole different ball game. The combo can be abused to give a euphoric high with an amount of phenylalanine you quite possibly wouldn’t even have noticed. The combo has also been used as a depression treatment. But either way selegiline + phenylalanine is powerful stuff. To the extent that I am surprised that people bother with illegal party drugs when this stuff is legal. (Above notes aside I am not particularly warning against selegiline + chocolate. There isn’t that much phenylalanine in the stuff that you’re going to get high. :P) Oh, and another thing. Selegiline is an irreversible MOAI-B. That means that when it deactivates the monoamine oxidase that molecule is deactivated for good. Basically, this means that the primary effect of selegiline operates over the timescale of about a month, not hours. It takes a while for the effects to build up and even longer for them to disappear completely. This is in stark contrast to most other things that give a stimulating effect. So don’t go about swallowing 500mg of phenylalanine a week after you stopped selegiline and be surprised when you hit the roof. 😉

[Btw, he meant phenylethylamine, not phenylalanine.]

I need this stuff. Only problem is that it’s so hard to get. In Europe it’s only prescribed for Parkinson’s disease. Although I’m a pretty good actor I can’t fake that. Even worse, it’s not available on REDACTED which is completely incomprehensible to me. Why is nobody interested in MAOIs? Apparently nobody has the balls to seriously mess up their biochemistry I guess.

Selegiline is still a pretty child-friendly toy since it only inhibits MAO-B. We want something even more drastic. Something that utterly annihilates your melancholic apathy for good. And there is a substance, so powerful and godlike its mere name makes your heart tremble with awe:

TRANYLCYPROMINE (PARNATE)

Gentleness doesn’t suit everyone. Moclobemide isn’t much good at lifting deep melancholy. Tranylcypromine (Parnate), on the other hand, is one of the older and non-selective MAOIs – and is often none the worse for it. Structurally related to amphetamine, tranylcypromine is generally the most stimulating, dopaminergic and relatively fast-acting of the MAOIs. Some doctors are uncomfortable with its properties. This isn’t just because of the dietary restrictions its use demands. In adequate doses, tranylcypromine tends to induce a mild euphoria even in “normal” subjects. Tranylcypromine use increases trace amines, modulates phospholipid metabolism and up-regulates GABA(B) receptors. In fact, its nicest effects, as for all of the compounds cited here, will vary in nature and extent from person to person. To some extent, optimal dosage and long-term drug-regimen of choice can be discovered only by (cautious) empirical self-investigation.

This just sounds like Eastern, Christmas and the Singularity combined. Needless to say, I would kill for this drug. And it get’s even better: It’s rather easy to obtain you-know-which-drug. It’s actually prescribed for depression in the EU and I don’t even have to fake depression. Oh, fuck, yes.

So my current plan is to first try Moclobemide. Then Selegiline. If I don’t die I’ll start with tranylcypromine and then live happily ever after.