Bad Noot Days, CRL40-940, Placebo, Nocebo
Daryl Seldon, MS, Therapist
I was sitting in undergrad Geology 1101 when I first noticed an issue. Dr. Spellman was doing his usual spiel, erosion, plate tectonics, volcanic rock swallowing Pompeii, and ravishing waters cutting mercilessly into the womb of North America, forming the Grand Canyon. I get it, in fact, I had gotten it since fourth grade, so the latest repeat was really boring the heck out of me. I stayed vigilant for one reason, Dr, Spellman was one of those professors who kept you awake by calling on random people to answer questions, and I surely didn’t want to look stupid in front of all these beautiful college girls. Suddenly, he pointed at me, “Mr. Seldon, what is the answer?” I was in a panic: I had not even heard the question! He looked at me, laughed, then did a complete backflip! It blew my mind! But, then I began to suspect it wasn’t real. And a good thing I did because I awoke to my hands flying onto the table automatically and catching me just before my head would have broken the table in half. I had fallen asleep in class and was merely dreaming that the old, fat professor had called on me then laughed and did a backflip.
I had noticed such problems formerly but just chalked it up to having a full course-load and one or two jobs. But this time, I decided to seek treatment with one of the college physicians. I had heard that modafinil would treat this problem. This was around 2004, so the drug was still somewhat knew, and despite my protests, he would not prescribe it. I don’t blame him.
Fast forward to 2014, Dave Asprey, somewhat of an internet age self-help guru was touting the benefits of modafinil, and on the news no less. Check out this clip.
I have to say, Dave looks to have aged rapidly, possibly due to stop-start cycles of steroids and modafinil. I remain generally skeptical of the guy as he has to sell products and sometimes does so by making claims he knows he can’t back up. He takes testosterone (he's admitted to it) and modafinil then sells people coffee and butter. In his defense, he has been very honest about what he takes but it does give the wrong impression when he says drink butter coffee and get the benefits I've gotten (with steroids and modafinil). But, I would do it too if I had the chance. I only point out that he has appeared to have aged rapidly because it might be a case study for people, like myself, who experiment with unknown substances. It is possibly just the stress of being a CEO or even just not having dyed his hair to appear older at board meetings. However, we need not pretend we may not see repercussions from our experimenting. Also, I'm not the only one who is a little uncomfortable with his methods, though I am inspired by him. Joe Rogan got into a spat about similar concerns.
I guess the problem with his approach is that when you fool people, you make those who support you look like a fool. When someone buys his spiel wholesale, I have to admit, my mind chalks them up to not terribly skeptical and kinda gullible.
I guess the problem with his approach is that when you fool people, you make those who support you look like a fool. When someone buys his spiel wholesale, I have to admit, my mind chalks them up to not terribly skeptical and kinda gullible.
None-the-less, I was sold on modafinil, but I needed something a little easier to obtain and which is non-scheduled so I chose a chemical cousin of modafinil, commonly called flmoda or CRL-40,940. Since this substance is not for human consumption nor would I want to give the impression that it is safe, I developed, researched, and compiled a case study of the compound from someone braver than I whom, knowing there are known and unknown risks and dubious legality, went and tried it anyway.
Case Study of CRL-40,940
An adult male, 33 yo, physically fit, good-looking, intelligent, and a generally all-around likeable personage and with few known health conditions complained of Excessive Daytime Sleepiness and obtained the compound CRL-40,940 to use as a wakefulness agent. To avoid dosing errors, he first tried 50 mgs, and added another 50 each day until symptoms of restlessness began to appear, which happened somewhere slightly above 200 mgs. The higher dose produced nervousness and akathisia so unpleasant the subject was loath to try doses beyond 200 mgs again.
The subject reported a paradoxical effect. The day of the first dose and each day of dosing afterwards appeared to produce an immediate sleepiness beyond the usual, and he found himself dozing off right after waking and dosing, then experiencing increased wakefulness late at night, when he would prefer to be asleep.
What could have happened? What kind of wakefulness agent puts you right to sleep? I checked the message boards for an explanation. I found reports of others who had experienced the same thing.
Surely this was a placebo effect. A friend corrected me, no, it is a ‘nocebo. response’.
What is a Nocebo Response?
(Jerry Seinfeld and Larry David, “Icon/Nocon skit”)
You have heard of a placebo response. It’s when a sham treatment produces real, positive benefits. A nocebo response is when a real or sham treatment produces negative effects which cannot be explained by the action of the substances administered but only by the psychological and psychosomatic state of the patient. One study by Harvard researcher Ted Kaptchuk that pit sham acupuncture against a sugar pill that subjects were told was a pain pill found that both sham treatments produced relief from intractable arm pain. Another study, found that patients received relief from sham treatments in a dose dependent manner, pending on how much care they received from their caregiver. A further study revealed that subjects improved on a placebo when told placebos can have positive effects even if they knew they were receiving a sham treatment.
Our subject in the case study appeared to experience increased sleepiness from taking a wakefulness agent and this is not a known or likely effect of the agent. Possibly the anticipation of wakefulness combined with the expectation that the agent would work like caffeine or amphetamine caused the subject to ‘let go’, expecting the agent to produce wakefulness that requires no effort, and not notice a different type of wakefulness brought on by this class of drugs. This would be a nocebo effect since nothing in the agent is causing the response but rather the psychological state of the subject after taking the substance is the cause.
The Bad Noot Day
The placebo and nocebo effects have particular application when it comes to nootropics. Many users of racetams and other substances often claim that the effect is subtle and takes weeks to notice. Skeptics then point to a placebo effect. If something only works subtly after months, it is probably only a placebo effect and not a very powerful one, they might say. However, a placebo response is not a problem because it still works. A nocebo response however could be a problem.
In other words, you could get a psychogenic negative effect. This needs to be outweighed by a clear and overt benefit, otherwise, people who may already be sensitive to psychogenic effects may begin to feel this particular nootropic isn’t working or worse is causing me to break out or is causing me to experience excessive daytime sleepiness as in our case study. "I’m having a bad noot day," in other words. If you’re using 10 noots and have come to believe they are all causing adverse reactions, withdrawals, or distressing thoughts, you become like a paranoid drug user, even though none of the substances you are using has anything in it that would cause this.
I have to admit, I have noticed nocebo effects using nootropics. The most common by far is the anxiety one gets when administering a new substance. You become quite naturally anxious and that is no direct effect of the substance administered but just a psychogenic response to taking something new. I have seen a wakefulness agent induce excessive sleepiness soon after administration, probably a nocebo response. I have felt nauseous after taking a substance only to discover later it could not have been as a result of the chemicals in the pill, but rather a result of nervousness from taking a new substance. If you find yourself having a bad noot day, know, this may be a nocebo effect. Perhaps there is something in your life producing anxiety and you have come to suspect your noots for the negative feelings you encounter. By being aware of placebo and nocebo effects, you can get the best out of your noots and the sky’s the limit.
"Dave Asprey on Provigil / Modafinil - YouTube." 2013. 6 Aug. 2015 <http://www.youtube.com/watch?v=zY7m5tYY3Cc>
"CRL-40,941 (Fladrafinil) - NewMind." 2014. 6 Aug. 2015 <https://newmind.com/crl-40-941.html>
"curb your enthusiasm - icon no con - YouTube." 2009. 6 Aug. 2015 <http://www.youtube.com/watch?v=olaXBUyrcZ0>
"The Placebo Effect: What Is It? - WebMD." 2012. 9 Aug. 2015 <http://www.webmd.com/pain-management/what-is-the-placebo-effect>
"Nocebo definition - MedicineNet - Health and Medical ..." 2005. 6 Aug. 2015 <http://www.medicinenet.com/script/main/art.asp?articlekey=31482>
Kaptchuk, TJ. "Sham device v inert pill: randomised controlled trial of two ..." 2006. <http://www.ncbi.nlm.nih.gov/pubmed/16452103>
Kaptchuk, Ted J et al. "Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome." Bmj 336.7651 (2008): 999-1003.
Kaptchuk, Ted J et al. "Placebos without deception: a randomized controlled trial in irritable bowel syndrome." PloS one 5.12 (2010): e15591.
