Effects of modafinil on cognitive performance (my bachelor thesis)

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I wrote my bachelor thesis about modafinil. Although it’s only a literature review I decided to publish some of its core findings on this blog.

Here are some relevant quotes:

Introduction: 

The subject of this bachelor thesis is, broadly speaking, cognitive enhancement. Bostrom and Roache (2010, p. 1) define cognitive enhancement as “the amplification or extension of core capacities of the mind through improvement or augmentation”. … The issue of cognitive enhancing substances is of considerable importance because many small individual improvements in cognitive performance could have profound effects at a societal level (Bostrom & Sandberg, 2009).

…the main research question of this thesis is if and to what extent modafinil has positive effects on cognitive performance (operationalized as performance improvements in a variety of cognitive tests) in healthy, non-sleep deprived individuals, substance-dependent individuals or patients with dementia. The abuse liability and adverse effects of modafinil are also discussed. A literature research of all available, randomized, placebo-controlled, double-blind studies which examined those effects was therefore conducted.

Overview of effects in healthy individuals:

…Altogether 19 randomized, double-blind, placebo-controlled studies about the effects of modafinil on cognitive functioning in healthy, non sleep-deprived individuals were reviewed. One of them (Randall et al., 2005b) was a retrospect analysis of 2 other studies (Randall et al., 2002 and 2005a), so 18 independent studies remain.

Out of the 19 studies, 14 found performance improvements in at least one of the administered cognitive tests through modafinil in healthy volunteers.
Modafinil significantly improved performance in 26 out of 102 cognitive tests, but significantly decreased performance in 3 cognitive tests.

…Several studies suggest that modafinil is only effective in subjects with lower IQ or lower baseline performance (Randall et al., 2005b; Müller et al., 2004; Finke et al., 2010). Significant differences between modafinil and placebo also often only emerge in the most difficult conditions of cognitive tests (Müller et al., 2004; Müller et al., 2012; Winder-Rhodes et al., 2010; Marchant et al., 2009).

Adverse effects: 

….A study by Wong et al. (1999) of 32 healthy, male volunteers showed that the most frequently observed adverse effects among modafinil subjects were headache (34%), followed by insomnia, palpitations and anxiety (each occurring in 21% of participants). Adverse events were clearly dose- dependent: 50%, 83%, 100% and 100% of the participants in the 200 mg, 400 mg, 600 mg, and 800 mg dose groups respectively experienced at least one adverse event. According to the authors of this study the maximal safe dosage of modafinil is 600 mg.

Abuse potential: 

…Using a randomized, double-blind, placebo-controlled design Rush et al. (2002) examined subjective and behavioral effects of cocaine (100, 200 or 300 mg), modafinil (200, 400 or 600 mg) and placebo in cocaine users….Of note, while subjects taking cocaine were willing to pay $3 for 100 mg, $6 for 200 mg and $10 for 300 mg cocaine, participants on modafinil were willing to pay $2, regardless of the dose. These results suggest that modafinil has a low abuse liability, but the rather small sample size (n=9) limits the validity of this study.

The study by Marchant et al. (2009) which is discussed in more detail in part 2.4.12 found that subjects receiving modafinil were significantly less (p<0,05) content than subjects receiving placebo which indicates a low abuse potential of modafinil. In contrast, in a study by Müller et al. (2012) which is also discussed in more detail above, modafinil significantly increased (p<0,05) ratings of “task-enjoyment” which may suggest a moderate potential for abuse.

…Overall, these results indicate that although modafinil promotes wakefulness, its effects are distinct from those of more typical stimulants like amphetamine and methylphenidate and more similar to the effects of caffeine which suggests a relatively low abuse liability.

Conclusion:

In healthy individuals modafinil seems to improve cognitive performance, especially on the Stroop Task, stop-signal and serial reaction time tasks and tests of visual memory, working memory, spatial planning ability and sustained attention. However, these cognitive enhancing effects did only emerge in a subset of the reviewed studies. Additionally, significant performance increases may be limited to subjects with low baseline performance. Modafinil also appears to have detrimental effects on mental flexibility.

…The abuse liability of modafinil seems to be small, particularly in comparison with other stimulants such as amphetamine and methylphenidate. Headache and insomnia are the most common adverse effects of modafinil.

…Because several studies suggest that modafinil may only provide substantial beneficial effects to individuals with low baseline performance, ultimately the big question remains if modafinil can really improve the cognitive performance of already high-functioning, healthy individuals. Only in the latter case modafinil can justifiably be called a genuine cognitive enhancer.

Happy by Habit [Happiness Sequence, Part 1]

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Summary: Becoming happier is a learnable skill, just like becoming more rational. Likewise, the best method to practice happiness is similar to the best method to train rationality: Practice only a few basic techniques very often, instead of trying hundreds of advanced techniques only a few times. This is the best way to install new cognitive habits that make you happier. And habits are crucial because will-power is limited. 

First of all, and often overlooked: Just like rationality, happiness is learnable. You can practice to be happier. Sure, for some people happiness is more difficult to achieve than for others, since genes account for about 50% of the variance in happiness1. Similarly, rationality skills are probably also heritable to a significant amount. Still, most people can learn to be happier.

Second of all, to become more rational you don’t have to practice hundreds of different, complicated and fancy rationality-techniques. No, there are probably less than ten, all-important, but rather simple rationality skills. E.g. being a good consequentialist and not falling prey to the sunk-cost-fallacy. (Writing this down it occurred to me, that there are indeed few basic rationality techniques, but each of them has lots of sub-techniques). Similarly, to become happier you don’t have to learn hundreds of complex, cognitive techniques for dealing with depressive thought patterns. You only have to learn some of them.

Thirdly, the most effective way to become more rational/happier is to practice those few basic techniques until they become second nature to you2. We can draw an analogy between practicing rationality/happiness-techniques and martial arts: To become a good martial arts fighter you should practice the basic kick and the basic defense over and over again, until you’re really great at kicking and defense. You should not try to spend most of your time practicing a 360° double-side kick which is only useful on very rare occasions3. By practicing a few, simple techniques every day, eventually those techniques should become habits. You don’t think about employing those techniques, you just do them automatically.

And habits are essential. Nobody has enough will-power to rely on to execute happiness-inducing techniques like e.g. meditating or cultivating gratitude every day anew. No, the only way is to practice one new technique until it becomes an automatic habit and you don’t even have to use will-power anymore to execute the habit. Then you have again enough will-power to focus on building the next technique4. An important caveat: Don’t try to establish too many new habits at a time. It’s probably better to focus on one or two new habits at a time and wait until they’ve become really easy to execute before you decide to learn a new habit.

What is the best way to install new habits (and get rid of bad old habits)? I’m too lazy to write about it here so I will link to this excellent post by Kaj Sotala. Also, I can highly recommend the book “Superhuman by Habit” which is probably the best and most inspiring book on the topic I’ve ever read.

In this post I write about some of the most effective strategies for dealing with depressive thought patterns. Of course, “most effective” is a relative term and those strategies are probably only suited to my idiosyncratic problems and personality.

[Next: Thoughts on Happiness (1)]

Footnotes:

1. Stubbe, Posthuma, Boomsa, & De Geus (2005). Heritability and life satisfaction in adults: A twin-family study. Psychological Medicine, 35: 1581-1588.

2. In this sequence I’m only discussing cognitive techniques for becoming happier. Fundamentals like exercise, good sleep and diet are arguably even more crucial in this regard.

3. Of course, this advice only applies to novices and intermediates in the art of rationality/happiness/martial arts. E.g. if you are already an expert and have mastered the basic fighting techniques you obviously should devote your time to more advanced techniques.

Ausweitung der Kampfzone

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“Ausweitung der Kampfzone” von Michel Houellebecq ist zweifellos ein Buch, das vor Nihilismus und Zynismus nur so trieft. Trotzdem – oder wahrscheinlich gerade deshalb – beschreibt es viele grausame Wahrheiten.

Houellebecq vermag den Geisteszustand apathischer Hoffnungslosigkeit und Anhedonie wie kein Zweiter zu beschreiben:

“Die Schwierigkeit ist, daß es nicht genügt, wenn Sie genau den Regeln entsprechend leben. Es gelingt Ihnen ja (wenn auch oft nur ganz knapp, aber alles in allem schaffen Sie es doch), den Regeln entsprechend zu leben. Ihre Steuererklärung ist in Ordnung. Die Rechnungen werden pünktlich bezahlt. Sie gehen nie ohne Personalausweis aus dem Haus (nicht zu vergessen: das kleine Etui für die Scheckkarte…).

Trotzdem haben Sie keine Freunde.

Die Regeln sind komplex und vielfältig. Außerhalb der Arbeitsstunden sind da die Einkäufe, die Sie wohl oder übel erledigen müssen, die Bargeldautomaten, von denen Sie Geld abheben müssen (und vor denen Sie oft Schlange stehen). Vor allem sind da die verschiedenen Zahlungen, die Sie den Institutionen zukommen lassen müssen, die die verschiedenen Aspekte Ihres Lebens verwalten. Zu allem Überfluß können Sie auch noch krank werden, was zusätzliche Kosten und Formalitäten mit sich bringt. Dennoch bleibt ein Stück Freizeit übrig. Was tun? Wie sie nützen? Vielleicht sich den Mitmenschen widmen? Aber im Grunde interessieren die Mitmenschen Sie kaum. Platten hören? Das war einmal eine Lösung, aber im Lauf der Jahre mußten Sie einsehen, daß Musik Sie von Mal zu Mal weniger berührt.

Basteln, im weitesten Sinne, könnte ein Weg sein. Aber in Wahrheit kann nichts die immer häufigere Wiederkehr jener Augenblicke verhindern, in denen Ihre absolute Einsamkeit, das Gefühl einer universellen Leere und die Ahnung, daß Ihre Existenz auf ein schmerzhaftes und endgültiges Desaster zuläuft, Sie in einen Zustand echten Leidens stürzen.

Trotzdem haben Sie immer noch keine Lust zu sterben.”

Besonders genial ist seine Technik, die Ernsthaftigkeit bedeutungsschwerer, existentieller Themen (“Gefühl einer universellen Leere”, “absolute Einsamkeit”) durch vorrangehende, lakonische formulierte Sätze trivialen Inhalts (“Basteln könnte ein Weg sein”) zu hintertreiben, was den Nihilismus des Romans umso mehr verstärkt.

Houellebecq vergleicht die sexuelle Revolution mit dem Kapitalismus und betont, dass beide negative Konsequenzen hatten:

“Der Sex, sagte ich mir, stellt in unserer Gesellschaft eindeutig ein zweites Differenzierungssystem dar, das vom Geld völlig unabhängig ist; und es funktioniert auf mindestens ebenso erbarmungslose Weise. Auch die Wirkungen dieser beiden Systeme sind genau gleichartig. Wie der Wirtschaftsliberalismus – und aus analogen Gründen – erzeugt der sexuelle Liberalismus Phänomene absoluter Pauperisierung. Manche haben täglich Geschlechtsverkehr; andere fünf oder sechs Mal in ihrem Leben, oder überhaupt nie. Manche treiben es mit hundert Frauen, andere mit keiner. Das nennt man das »Marktgesetz«. In einem Wirtschaftssystem, in dem Entlassungen verboten sind, findet ein jeder recht oder schlecht seinen Platz. In einem sexuellen System, in dem Ehebruch verboten ist, findet jeder recht oder schlecht seinen Bettgenossen. In einem völlig liberalen Wirtschaftssystem häufen einige wenige beträchtliche Reichtümer an; andere verkommen in der Arbeitslosigkeit und im Elend. In einem völlig liberalen Sexualsystem haben einige ein abwechslungsreiches und erregendes Sexualleben; andere sind auf Masturbation und Einsamkeit beschränkt. Der Wirtschaftsliberalismus ist die erweiterte Kampfzone, das heißt, er gilt für alle Altersstufen und Gesellschaftsklassen. Ebenso bedeutet der sexuelle Liberalismus die Ausweitung der Kampfzone, ihre Ausdehnung auf alle Altersstufen und Gesellschaftsklassen.”

Auf die Nachteile des Kapitalismus zu verweisen, ist in den meisten Kreisen kein Problem, ja zeugt von Fortschrittlichkeit und Mitgefühl. Doch sobald man versucht, die Nachteile der sexuellen Revolution zu erwähnen, wird man entweder als lustfeindlicher Puritaner oder als sexueller Versager angesehen. Oder beides. Was ja meist auch zutrifft.

“Ein seltenes, künstliches und spätes Phänomen, blüht die Liebe nur unter besonderen geistigen Voraussetzungen, die selten zusammentreffen und in jeder Hinsicht der Sittenfreiheit, die das moderne Zeitalter charakterisiert, entgegengesetzt sind. Véronique hatte zu viele Diskotheken und Liebhaber kennengelernt. Eine solche Lebensweise läßt das menschliche Wesen verarmen, sie fügt ihm Schäden zu, die manchmal schwerwiegend und stets irreparabel sind. Die Liebe als Unschuld und Fähigkeit zur Illusion, als Gabe, die Gesamtheit des anderen Geschlechts auf ein einziges geliebtes Wesen zu beziehen, widersteht selten einem Jahr sexueller Herumtreiberei, niemals aber zwei. In Wirklichkeit zerrütten und zerstören die zahllosen, während der Zeit des Heranwach- sens angehäuften sexuellen Erfahrungen jede Möglichkeit gefühlsmäßiger, romantischer Projektion. Nach und nach, tatsächlich aber sehr rasch, wird man so liebesfähig wie ein altes Wischtuch. Man führt dann unvermeidlich ein Wischtuchleben; mit fortschreitendem Alter wird man weniger verführerisch, und in der Folge verbittert. Man ist eifersüchtig auf die Jungen und haßt sie daher. Dieser Haß, der uneingestanden bleiben muß, wird bösartig und immer brennender; schließlich mildert er sich und verlöscht, wie alles verlöscht. Es bleiben nur noch Verbitterung und Ekel, Krankheit und Warten auf den Tod.”

Sicherlich ist ein Zurück zu den “guten alten Zeiten” auch keine Lösung. Die Vorteile der sexuellen Revolution überwiegen wahrscheinlich deren Nachteile; wie dies ja auch beim Kapitalismus der Fall ist.

Fazit? Das Leben ist – nach wie vor – hart. Daran wird sich ohne radikale Maßnahmen  auch nicht viel ändern.

Drug side effects are underreported

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It’s old news that our medical system isn’t the most reliable truth-finding enterprise ever invented. Recently I stumbled over a concrete example that even surprised me. 

I searched on google scholar for side effects of zopiclone, a supposedly safe, relatively new hypnotic. With 123 citations on google scholar, one of the most promising hits was this review (Terzano et al., 2003) of the side effects and tolerability of the so called Z-drugs (zolpidem, zaleplon and zopiclone). For comparison, this rather unfavorable meta-analysis of the Z-drugs by Joya et al. (2009) has only 3 citations.

After reading the first few pages doubts about the credibility of this paper already emerged. They write:

Zopiclone appears to be well tolerated….. The most commonly reported adverse event is bitter taste, found in 5 out of 49 (Tamminen & Hansen, 1987) and 8 out of 37 patients (Anderson, 1987) in various studies.

Literally everyone I know (about 7 people) who has taken zopiclone is disgusted by its bitter taste. This made me obviously suspicious of the whole study. But maybe I know only unusually sensitive people.

But it get’s worse:

In a large postmarketing surveillance study on 20513 patients (Allain et al., 1991) no serious adverse events were reported. The overall percentage of reported events was 9,2%. The most frequent were bitter taste (3,64%), dry mouth (1,6%), difficulty arising in the morning (1,3%) and daytime sleepiness (0,5%).

Only 1,3% reported ‘difficulty arising in the morning’ and only 0,5% reported ‘daytime sleepiness’! Way more than that percentage of healthy individuals who don’t take any drugs experience difficulty arising in the morning or daytime sleepiness on any given day. The only possibility is that the authors operationalized those constructs in such a ridiculous way that e.g. ‘daytime sleepiness’ meant something like literally falling asleep while driving to work and crashing. Which would make this study pretty useless, obviously.

As a side note, SSRIs present us with a similar phenomenon. Initial studies which relied on spontaneous reporting methods found that sexual side effects where only reported by less than 10% of all patients. However, newer studies which did not rely on unprompted reporting methods found that up to 80% of patients experienced sexual side effects (Serretti & Chiesa, 2009).

Thus, we can conclude that many drug side effects go unnoticed. In the case of sexual dysfunction this can be easily explained. Many depressed people were probably too embarrassed to talk about their sex-life. But bitter taste or daytime sleepiness?

Besides bizarre operationalizations and the usual suspects like e.g. publication bias or skewed incentives I can think of a few other explanations. Maybe patients are intimidated by their doctors and don’t dare to question the safety of the holy pills handed to them by these high-status people in white coats. Maybe they are simply too lazy to report side effects, because they would have to stay longer and complete more questionnaires.

Perhaps many patients report these side effects, but the doctors are too lazy to write them down or don’t take these reports seriously.

Regardless of how this phenomenon of underreported adverse events can be explained, one should be wary of new drugs which are supposedly safe and without side effects. I only became suspicious of this review because I had first hand experience with the drug. If it had been a drug I had never taken I probably wouldn’t have noticed that there is something fishy about this whole review.

Allain, H., Delahaye, C. H., Le Coz, F., Blin, P., Decombe, R., & Martinet, J. P. (1991). Postmarketing surveillance of zopiclone in insomnia: analysis of 20,513 cases. Sleep, 14(5), 408.

Anderson, A. A. (1987). Zopiclone and nitrazepam: a multicenter placebo controlled comparative study of efficacy and tolerance in insomniac patients in general practice. Sleep, 10, 54.

Billiard, M., Besset, A., De Lustrac, C., Brissaud, L., & Cadilhac, J. (1989). Effects of zopiclone on sleep, daytime somnolence and nocturnal and daytime performance in healthy volunteers. Neurophysiologie clinique= Clinical neurophysiology, 19(2), 131.

Joya, F. L., Kripke, D. F., Loving, R. T., Dawson, A., & Kline, L. E. (2009). Meta-analyses of hypnotics and infections: eszopiclone, ramelteon, zaleplon, and zolpidem. Journal of clinical sleep medicine: JCSM: official publication of the American Academy of Sleep Medicine, 5(4), 377.

Serretti, A., & Chiesa, A. (2009). Treatment-emergent sexual dysfunction related to antidepressants: a meta-analysis. Journal of clinical psychopharmacology, 29(3), 259-266.

Tamminen, T., & Hansen, P. P. (1987). Chronic administration of zopiclone and nitrazepam in the treatment of insomnia. Sleep, 10, 63.

Terzano, M. G., Rossi, M., Palomba, V., Smerieri, A., & Parrino, L. (2003). New drugs for insomnia: comparative tolerability of zopiclone, zolpidem and zaleplon. Drug Safety, 26(4), 261-282.

The Good Drug Guide and the Holy Grail of Chemical Paradise: MAOIs

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[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.

Pessimistische Psychotherapie I

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[Diese Abhandlung ist offensichtlich von weinerlichem existentialistischem Gedankengut inspiriert. Und ich bin natürlich auch nicht der erste, der auf eine fruchtbare Verknüpfung von Existentialismus und Psychotherapie hinweist. Zu einiger Bekanntheit gelang beispielsweise die existentielle Psychotherapie von Irvin Yalom. Allerdings war Yalom noch ziemlich von der Psychoanalyse beeinflusst und ignoriert meines Wissens nach viele neuere psychologische Erkenntnisse. Mein Ziel ist hier gewissermaßen die Kombination von existentialistisch-pessimistischer Philosophie und evolutionärer Psychologie.]

Der Großteil der Psychotherapeuten – und auch der Menschen im Allgemeinen – ist der Meinung, dass die Existenz grundsätzlich etwas Gutes ist und dass folglich mit Depressiven etwas nicht stimme, dass sie die Schönheit der Welt verkennen, gewissermaßen existentiell blind sind.

Ich bin anderer Meinung. Denn häufig sind gerade die Glücklichen die Blinden. Sie verschließen vor dem Elend unserer Welt die Augen, wagen nicht, die Schleier ihrer Wahrnehmung zu lichten und suhlen sich im Schlamm ihrer optimistisch-verblendeten Weltanschauungen. (Verzeiht das übertriebene Pathos.)
Depressive hingegen haben in den Abgrund geblickt und können oder wollen nicht mehr vergessen, was sie gesehen haben. Sie mit naivem Eifer zu drängen, sich mit panglossianischen Lügengebäuden zu trösten – wie es die meisten Religionen und viele Formen des Humanismus nun einmal sind  – wird nur ihre Gefühle des Unverstandenseins und der Einsamkeit verstärken. Viel effektiver und ehrlicher ist es, auf ihre Sicht der Dinge einzugehen und anzuerkennen (und sei es nur vorläufig), dass das Leben in diesem für menschliche Bedürfnisse und Träume tauben Universum kein Ponyhof ist. Danach kann man immer noch versuchen zu erklären, warum es sich dennoch zu leben und zu kämpfen lohnt.

Genau das ist das Ziel der folgenden Posts. Beginnen wir also mit dem ersten der fundamentalen Mängel der menschlichen Existenz.

1. Sozialer Status:  

Menschen, insbesondere männlichen Geschlechts, hegen den Wunsch hohen Status zu erlangen, von anderen beachtet und bewundert zu werden. Das Bedürfnis nach Anerkennung ist fast genauso elementar und notwendig für die eigene Zufriedenheit wie ein gefüllter Magen. Das sollte auch nicht verwundern. Diejenigen unserer Vorfahren, welche den Drang nach Status nicht hatten, haben folglich auch nichts getan, um selbigen zu erhöhen. Doch ohne sozialen Status bleibt unter anderem der Zugang zu paarungswilligen, fruchtbaren Weibchen versperrt und die Status-Indifferenten gaben folglich ihre Gene nicht weiter. Die evolutionäre Psychologie kann somit erklären, warum es so schwer ist, den Wunsch nach Anerkennung und Respekt zu unterdrücken, auch wenn dies erklärtes Ziel vieler Religionen oder anderer Psycho-Gurus ist. Wem das Abtöten des Wunsches nach sozialem Status in buddhistischer Manier nicht gelingt (und das schaffen die wenigsten), muss erkennen, dass er mit einer Quelle kontinuierlicher Frustration konfrontiert ist.

Bedauerlicherweise wird man an die eigene Mittelmäßigkeit nicht nur in vereinzelten Situationen erinnert. Nein, unaufhörlich und überall wird einem die eigene Mediokrität unter die Nase gerieben.

Werbung und Modezeitschriften halten uns täglich vor Augen, dass es Menschen gibt, die in jeder Hinsicht besser aussehen. Diese ästhetischen Übermenschen sind schlanker, muskulöser und größer; zudem mit makellosen, attraktiven Gesichtern gesegnet. Wie sollen wir da mit unseren 0815-Gesichtern und unseren von Speckschichten übersäten Körpern mithalten?  Nun gut, nicht so schlimm, wir sind ja Intellektuelle und keine oberflächlichen, vom Körperkult besessenen Teenies.

Aber leider legen viele Männer nun einmal höchsten Wert auf das Äußere und können schlichtweg keine romantischen Beziehungen mit Frauen anfangen, die ihren optischen Maßstäben nicht entsprechen. Und das nicht aus vorsätzlicher Grausamkeit. Die meisten Männer würden ihre ästhetischen Präferenzen wahrscheinlich transformieren, um sie auf diejenige Frau mit der tollsten Persönlichkeit anzupassen. Doch diese primitiven Triebe kann man so wenig verändern wie seine eigene sexuelle Präferenz. Ich wäre schon längst schwul oder zumindest bisexuell, wenn das möglich wäre. Wir sind Sklaven unserer Passionen. Das Ganze führt also zu viel Leid und Unzufriedenheit auf beiden Seiten. Die Männer sind mit der Attraktivität der eigenen Partnerin unzufrieden, bekommen schließlich Erektionsstörungen und schämen sich auch noch für ihre Primitivität. Die Frauen wissen Bescheid und haben Angst, dass ihr Partner sie irgendwann einmal nicht mehr begehrt und für eine hübschere Frau verlässt. Doch dazu mehr in einem späteren Post.

Im ökonomischen Sektor spielt sich Ähnliches ab. Andauernd werden wir mit Bildern von Segelyachten, Ferraris, Villen auf Sizilien und den neuesten Apple-Gadgets bombardiert, was uns vor Augen führt, wie wenig wir uns davon eigentlich leisten können. Mich persönlich schert das wenig, aber für die meisten Menschen ist es eine Qual. (Das schwache Geschlecht ist im vorherigen Absatz etwas besser weggekommen, aber das wird durch die folgenden Zeilen wieder ausgeglichen.)

Die meisten Männer streben vermutlich vor allem deswegen nach Reichtum und Macht, weil sie instinktiv wissen, dass viele Frauen darauf stehen. Ostentativer Konsum wird zwar oft belächelt, ist aber leider trotzdem ziemlich effektiv. Also versuchen die meisten immer und immer reicher zu werden und mehr und mehr Statussymbole anzuhäufen. Um sich das leisten zu können, muss man natürlich unzählige Stunden in einem monotonen Drohnen-Job absitzen. Doch dieses Rattenrennen hört nie auf. Es wird immer reichere Menschen geben. Man(n) lebt mit der ständigen Angst, dass einen seine Partnerin aufgrund ihrer hypergamen Instinkte für einen Millionär mit höherem Status verlässt, denn in unseren Zeiten ist die Scheidung ja nicht mehr wirklich verpönt.

Glücklicherweise haben wir Intellektuelle ja andere Maßstäbe und beugen uns nicht den Werten unserer materialistischen Mainstream-Kultur. Intelligenz, Bildung und Weisheit sind uns wichtiger als Reichtum und Wohlstand. Aber hier stoßen wir auf das selbe Problem.

Meine narzisstische Seite drängt mich persönliche Erfahrungen anzuführen: In meiner von Unbekümmertheit und Naivität geprägten Jugend träumte ich häufig davon, irgendwann einmal ein berühmter Wissenschaftler oder Philosoph zu werden. In der Schule gaben mir Lehrer und Mitschüler das Gefühl, ein kleines Genie zu sein. Auf der Universität wurde ich dann jedoch eines Besseren belehrt. Auf einmal war ich nicht mehr der King, und das obwohl ich viel mehr lernte als in der Schule. Manche meiner Kommilitonen hatten bessere Noten und besaßen ein umfassenderes Verständnis der Materie als ich, und das obwohl sie sich weniger anstrengten. Sie waren schlichtweg begabter. Da ich meinen Selbstwert vor allem über meine Intelligenz und mein Wissen bezog, war diese Erkenntnis natürlich ein Schlag ins Gesicht. Ein großer Teil meines Selbstkonzepts ging in diesen dunklen Monaten zu Grunde.

Mit 15 IQ-Punkten mehr wäre ich vielleicht Physik-Professor geworden, aber auch hier bleibt das Problem bestehen. Es wird (fast) immer Menschen geben, die intelligenter sind als man selbst, mehr wissenschaftliche Veröffentlichungen vorweisen können, mehr revolutionierende Theorien entwickelt haben. Erst ab dem Level von Einstein oder Neumann dürfte die Sache ein Ende haben.

Das Gleiche gilt fürs Schreiben. Ich empfinde meinen Schreibstil oft als schwerfällig und plump. Zudem schreibe ich auch noch unendlich langsam und feile bisweilen Ewigkeiten an irgendeinem Nebensatz. Mir fehlt schlichtweg die Fähigkeit meine Gefühle und Gedanken treffend auszudrücken. Gott sei Dank habe ich schon früh den Traum vom Schriftsteller-Dasein aufgegeben, aber ähnlich müssen sich angehende Künstler fühlen. Sie haben etwas zu sagen, können es aber nicht. Als ob sie stumm wären. Und obendrauf sind sie ständig mit literarischen Meisterwerken konfrontiert, zudem arm, allein und unbekannt.

Ähnliches trifft natürlich auf Kunst, Musik, Sport und alle anderen möglichen Bereiche, Berufe und Tätigkeiten zu. Ihr versteht das Konzept, deshalb gehe ich nicht mehr im Detail darauf ein. Egal auf welchem Gebiet, es wird immer Menschen geben, die besser und begabter sind, mehr erreicht haben, höheren Status haben als man selbst. Und Dank der globalen Vernetzung konkurrieren wir heute wirklich mit der ganzen Menschheit. Vor 10.000 Jahren, in der Umwelt der evolutionären Angepasstheit gab es vermutlich noch einen anderen Ausweg. Hier mag es noch möglich gewesen zu sein, eine Nische zu finden, in der man tatsächlich der Allerbeste war, da der eigene Clan ja nur aus ein paar Dutzend Leuten bestand. Sicher, es gab dennoch extreme Status-Hierarchien, aber vielleicht war man der beste Jäger, oder der beste Holzschnitzer oder der beste Kleidungsmacher. Irgendwo konnte man schon brillieren.

Klar, auch heute wird man noch Tätigkeiten oder Freizeitbeschäftigungen finden, die von so wenigen Menschen betrieben werden, dass man aufgrund der geringen Konkurrenz der Beste sein kann. Aber wen interessiert es schon, dass man Weltmeister im Hot-Dog-Wettessen-ohne-Hände-auf-LSD ist?

Um die Sache etwas aufzulockern, erwarten euch in den nächsten Posts Alter und Krankheit, Tod und Vergänglichkeit, existentielle Isolation, die Unmöglichkeit “wahrer Liebe”, sowie Sinnlosigkeit und Absurdität.

See also: Rank Theory