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Adderall Risks: Much More Than You Wanted To Know

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[Previously in series: Antidepressant Pharmacogenomics: Much More Than You Wanted To Know; SSRIs: Much More Than You Wanted To Know, etc. This is all preliminary and you should not take it as a reason to change successful medical care. None of this necessarily applies to your particular case and you should talk to your doctor if you have questions about that.]

I. Confessions Of A Gatekeeper

I didn’t realize how much of a psychiatrist’s time was spent gatekeeping Adderall.

The human brain wasn’t built for accounting or software engineering. A few lucky people can do these things ten hours a day, every day, with a smile. The rest of us start fidgeting and checking our cell phone somewhere around the thirty minute mark. I work near the financial district of a big city, so every day a new Senior Regional Manipulator Of Tiny Numbers comes in and tells me that his brain must be broken because he can’t sit still and manipulate tiny numbers as much as he wants. How come this is so hard for him, when all of his colleagues can work so diligently?

(it’s because his colleagues are all on Adderall already – but telling him that will just make things worse)

He goes on to give me his story about how he’s at risk of getting fired from his Senior Regional Manipulator Of Tiny Numbers position, and at this rate he’s never going to get the promotion to Vice President Of Staring At Giant Spreadsheets, so do I think I can give him some Adderall to help him through?

Psychiatric guidelines are very clear on this point: only give Adderall to people who “genuinely” “have” “ADHD”.

But “ability to concentrate” is a normally distributed trait, like IQ. We draw a line at some point on the far left of the bell curve and tell the people on the far side that they’ve “got” “the disease” of “ADHD”. This isn’t just me saying this. It’s the neurostructural literature, the the genetics literature, a bunch of other studies, and the the Consensus Conference On ADHD. This doesn’t mean ADHD is “just laziness” or “isn’t biological” – of course it’s biological! Height is biological! But that doesn’t mean the world is divided into two natural categories of “healthy people” and “people who have Height Deficiency Syndrome“. Attention is the same way. Some people really do have poor concentration, they suffer a lot from it, and it’s not their fault. They just don’t form a discrete population.

Meanwhile, Adderall works for people whether they “have” “ADHD” or not. It may work better for people with ADHD – a lot of them report an almost “magical” effect – but it works at least a little for most people. There is a vast literature trying to disprove this. Its main strategy is to show Adderall doesn’t enhance cognition in healthy people. Fine. But mostly it doesn’t enhance cognition in people with ADHD either. People aren’t using Adderall to get smart, they’re using it to focus. From Prescription stimulants in individuals with and without attention deficit hyperactivity disorder:

It has never been established that the cognitive effects of stimulant drugs are central to their therapeutic utility. In fact, although ADHD medications are effective for the behavioral components of the disorder, little information exists concerning their effects on cognition…stimulant drugs do improve the ability (even without ADHD) to focus and pay attention.

I cannot tell you how much literature there is trying to convince you that Adderall will not help healthy people, nor how consistently college students disprove every word of it every finals season.

That makes “only give Adderall to people with ADHD” a moral judgment, not a medical one. Adderall doesn’t “cure” the “disease” of ADHD, at least not in the same way penicillin cures syphilis. Adderall will give everyone better concentration, and we’ve judged that it’s okay for people with terrible concentration to use it to overcome their handicap, but not okay for people with already-fine concentration to use it to become superhuman.

We could still have a principled definition of ADHD. It would be something like “People below the 5th percentile in ability to concentrate, as measured by this test.” Instead, we use the DSM, which advises us to diagnose people with ADHD if they say they have at least five symptoms from a list. The list has things like “often has difficulty sustaining attention” and “often has difficulty organizing tasks”. How often? You know, often! And if you work as a Senior Regional Manipulator Of Tiny Numbers, you’re going to have attention problems a lot more “often” than the rest of us.

So the DSM criteria are kind of meaningless, but that’s fine, because people can just lie about them anyway.

There are whole websites for this: How To Convince Your Shrink You Have ADHD, How To Get Your Doctor To Prescribe You Adderall In Five Easy Steps, et cetera. But I can’t imagine most people need them. Just talk about all the times in your life that you had attention and concentration problems, and if your doctor asks you a more specific question (“Do you often lose things?”) you give the obvious right answer (“Wow, it’s like you’ve known me my whole life!”).

Aren’t psychiatrists creepy wizards who can see through your deceptions? There are people like that. They’re called forensicists, they have special training in dealing with patients who might be lying to them, and they tend to get brought in for things like evaluating a murderer pleading the insanity defense. They have a toolbox of fascinating and frequently hilarious techniques to ascertain the truth, and they’re really good at their jobs.

But me? At best, I can have a vague suspicion you’re not telling the truth. And how many patients genuinely in need of treatment do I want to risk accidentally rejecting just so I can be sure of thwarting you? A lot of 100% honest psychiatric patients’ stories are pretty unbelievable, really, and I don’t want to have to treat every patient like a convicted murderer. Unless you give me some specific reason to doubt you, I start with the assumption that you’re telling the truth.

Think about how wasteful all of this is. We throw people in jail for using Adderall without a prescription. We expel them from colleges. We fight an expensive and bloody War on Drugs to prevent non-prescription-holders from getting Adderall. We create a system in which poor people need to stretch their limited resources to make it to a psychiatrist so they can be prescribed Adderall, in which people without health insurance can never get it at all, in which DEA agents occasionally bust down the doors of medical practices giving out Adderall illegally. All to preserve a sham in which psychiatrists ask their patients “Do you have ADD symptoms?” and the patients say “Oh, yeah, definitely,” and then the psychiatrists give them Adderall. It’s like adding twenty layers of super-reinforced concrete to a bunker with a wide-open front door.

(Also, if by some chance a psychiatrist doesn’t give a patient Adderall, that patient practically always goes to another psychiatrist, and that next psychiatrist does. Trust me, no matter how unsuitable a candidate you are, no matter how bad a liar you are, somewhere there is a psychiatrist who will give you Adderall. And by “somewhere”, I mean it will take you three tries, tops.)

Psychiatrists’ main response to this perverse and unwinnable system is to give people Adderall, but feel guilty about it. Somebody should do an anthropological study on this, but my preliminary observations:

Some people will lecture their patients on how Medication Can Never Address The Root Cause Of A Problem, and the patient will agree that Medication Can Never Address The Root Cause Of A Problem, and then the psychiatrist will give them Adderall and feel good about it.

Some people will discuss alternative options, like behavioral treatments, or non-stimulant medications, and the patient will come back in a month and say that the behavioral treatments didn’t work, and then the psychiatrist will give them Adderall and feel good about it.

Some people will give their patients a formal test where they have to answer questions like “I often have trouble concentrating – strongly disagree, disagree, neutral, agree, or strongly agree?” Then the patient will give whatever answers get them Adderall, the psychiatrist will add up all the answers and score the test and find that it means the patient needs Adderall, and then the psychiatrist will give the patient Adderall and feel good about it.

Some people will occasionally find some little issue with one patient’s story, deny them Adderall, and then ride out the moral high for weeks, feeling so virtuous that they can give the next few people Adderall and feel good about it.

Some people will demand multiple evaluation sessions, lots of laboratory tests, make a patient tell them their whole life story. And after learning that they had a bad relationship with their stepfather in 8th grade and still have sexual hangups over that time they ejaculated prematurely with Sally one time in freshman year, the psychiatrist will give the patient Adderall and feel good about it.

I have been guilty of all of these at one time or another. I still wrestle with these issues a lot. The latest step in my evolving position was reading Kelsey’s blog post about having ADHD and trying to get Adderall. Her doctor gave her a list of things she had to do before he would give her Adderall, and she – having ADHD – got distracted and never did any of them.

(by my calculations, that decreased Kelsey’s effectiveness by 20%, thus costing approximately 54 billion lives.)

So lately I’ve been trying to be smarter about all this. What about good old consequentialism? Most people will get some benefit from Adderall, but it’s a powerful drug with a lot of potential risks. Maybe I should figure out exactly how bad the risks are, and then I can figure out how bad people’s concentration problems would have to be for the risks to be outweighed by the benefits.

Trying to discover the risks of Adderall is a kind of ridiculous journey. It’s ridiculous because there are two equal and opposite agendas at work. The first agenda tries to scare college kids away from abusing Adderall as a study drug by emphasizing that it’s terrifying and will definitely kill you. The second agenda tries to encourage parents to get their kids treated for ADHD by insisting Adderall is completely safe and anyone saying otherwise is an irresponsible fearmonger. The difference between these two situations is supposed to be whether you have a doctor’s prescription. But what if you are the doctor, trying to decide who to prescribe it to? Then what? All they tell you in medical school is to give it to the people who actually have ADHD – which, I repeat, is kind of meaningless.

This post records my attempt to figure out something better. Apologies for the length.

II. Medical Risks

Most people on stimulants will have some minor side effects. Feeling jittery, feeling cold, feeling sick, leg cramps, arm cramps. Some will feel “like a robot” or otherwise psychologically uncomfortable. But these don’t discourage me from giving stimulants to people who need them. If someone needs the drugs, let them try them, see how many side effects they get, and decide for themselves whether it’s worth it.

I’m much more concerned about side effects that are permanent and dangerous. These people give us a list:

Sounds pretty bad. On the other hand, I’ve prescribed Adderall to lots of people and none of them have ever gotten any of these things, except mild hypertension. How common are these, really?

The best source for exact numbers is the guidelines by sinister-sounding European organization EUNETHYDIS. I’ll use US medical database UpToDate as a secondary source. Both lump together Adderall and Ritalin – something I’ll be doing too throughout most of this essay, except where it becomes important to distinguish them.

Seizures: EUNETHYDIS doesn’t believe this happens at normal doses. They write:

There are occasionally concerns that, as with other psychotropics, ADHD medications may lower the seizure threshold so as to cause seizures in previously seizure-free individuals. However, in prospective trials, retrospective cohort studies and post-marketing surveillance in ADHD patients without epilepsies, the incidence of seizures did not differ between ADHD pharmacotherapy and placebo [relative risk (RR)] for current versus non-use for methylphenidate, 0.8; RR for atomoxetine, 1.1

UpToDate is so unimpressed by this that they don’t even mention it. If you ask them about seizure risk for ADHD medications, they start telling you about bupropion. Overall I wouldn’t give these medications to people with a known seizure disorder without a neurologist’s approval, but they seem pretty okay otherwise.

Hypertension: Broad agreement from both sources that stimulants cause hypertension. EUNETHYDIS says 1-4 mm systolic, UpToDate says 3-8 mm.

The main problem with hypertension is that it increases risk for things like heart attacks. I calculated an average 40 year old’s risk of heart attack and got 1% over 10 years. Adding on an average Adderall-related increase in blood pressure, I got 1.1%.

What about in high-risk adults? I calculated risk for a 60 year old smoker with high cholesterol and high blood pressure. He has a 30.5% base risk of heart attack. Then I added in a typical Adderall-related rise in blood pressure, and he ended up at 32.0%. So Adderall only increased risk by about 1/1000 per year, even in this worst case scenario. Also, I never meet 60 year old smokers asking for Adderall. Overall this seems not too interesting.

I haven’t looked into other hypertension-related problems like kidney disease as much, but these seem like things you’ll hopefully have a lot of warning about and be able to talk to your doctor about whether to stop stimulants over.

Heart Attack and Stroke: My usual sources fail me here, but BioMed Central Cardiovascular Disorders comes to the rescue. They review three major studies on stroke and heart attack in stimulant patients.

Study #1 finds that stimulant users have 3x more risk of transient ischaemic attack (a small mini-stroke that does no lasting damage), but no increased risk of stroke.

Study #2 is the best and biggest study, and finds that stimulants actually reduce heart attack and stroke. They suspected “healthy-user bias”; that is, only healthy people would use such a supposedly-dangerous medication.

Study #3 is the most recent, and found no increased risk of heart attack or stroke.

UpToDate writes:

Patients receiving stimulant therapy visited the emergency department or clinician office more frequently than those who were not treated with medications because of cardiac symptoms (10.9 versus 9.1 events per 1000 patient-years, adjusted hazards ratio 1.2, 95% CI 1.04-1.38) [26]. The cardiac symptoms included syncope, tachycardia, or palpitations. However, the group that received stimulant therapy was more likely to receive other psychotropic medications (antidepressants and antipsychotic agents), be male, and be non-Hispanic. The incidence of fatal and serious cardiac abnormalities was low and not different between the two groups, and was similar to the rates seen in the general pediatric population.

The 1/1000 extra ER visit per patient year sounds bad, but “palpitations” means “your heart feels like it’s beating in a weird way”, and Adderall clearly causes this, so my guess is this is mostly just people feeling this and freaking out. I have had patients call me after feeling this and freaking out, and we dealt with it, and they were fine. If I hadn’t been available, maybe they would have gone to the ER and turned themselves into a statistic.

There might be some bias in these studies, but overall there doesn’t seem to be much evidence this is worth worrying about unless your risk of heart attack or stroke is already really high.

Psychosis: I saw this a lot when I worked in inpatient. Somebody would take five times the recommended dose, or take more Adderall every time they felt tired until they hadn’t slept for a week, and then they would start hearing voices or feeling like something was crawling on their skin. After a day or two off Adderall, and a night or two getting a normal amount of sleep, they’d be fine. Take enough stimulants and you will become psychotic – but it’s rare on prescribed doses, and it usually resolves pretty quickly.

What dose can cause psychosis? Amphetamine-Induced Psychosis says:

Early studies demonstrated that amphetamines could trigger acute psychosis in healthy subjects. In these studies, amphetamine was given in consecutively higher doses until psychosis was precipitated, often after 100–300 mg of amphetamine. The symptoms subsided within 6 days.

Compare this to the standard daily dose of Adderall of about 10 – 60 mg.

Can psychosis ever happen at normal doses? EUNETHYDIS is skeptical. They write:

Data from population-based birth cohorts indicate that self-reported psychotic symptoms are common and may occur in up to 10% of 11-year-old children. In contrast, the prevalence of psychotic symptoms in children treated with ADHD drugs from RCTs is reported as only 0.19%. While this very low observed event rate in trials is likely to reflect a lack of systematic assessment and reporting, there is no compelling evidence to suggest that the observed event rate of psychotic symptoms in children treated with ADHD drugs exceeds the expected (background) rate in the general population. In the US FDA analysis, ADHD drug overdoses did not contribute significantly to reports of psychosis adverse events.

So basically, “kids are always kind of weird, studies say kids aren’t weird on Adderall, clearly they’re not paying attention, but it doesn’t look like things got any worse.”

UpToDate links these people, who say:

We analyzed data from 49 randomized, controlled clinical trials in the pediatric development programs for these products. A total of 11 psychosis/mania adverse events occurred during 743 person-years of double-blind treatment with these drugs, and no comparable adverse events occurred in a total of 420 person-years of placebo exposure in the same trials. The rate per 100 person-years in the pooled active drug group was 1.48. The analysis of spontaneous postmarketing reports yielded >800 reports of adverse events related to psychosis or mania. In approximately 90% of the cases, there was no reported history of a similar psychiatric condition. Hallucinations involving visual and/or tactile sensations of insects, snakes, or worms were common in cases in children.

I think their use of “psychotic events per person-year” is misleading. Their study includes 5717 people, which means that for them to have 743 person-years each person must have been monitored for two months or so. But if you’re going to get psychotic on stimulants, usually it’s right after the stimulant is started. That means it might be better framed as “11/5717 patients had a psychotic event”, or even “one in every five hundred patients had a psychotic event”. Note that this matches the 0.19% number given by EUNETHYDIS. And the most common psychotic event was a feeling of snakes or insects on the skin which resolved after the drug was stopped, so we’re not talking “person is forever schizophrenic” here.

Also, I feel like EUNETHYDIS makes a good point with the “kids are always weird” thing. Here’s one of the psychotic events mentioned in the paper:

A spontaneous report from the manufacturer of Strattera (atomoxetine) described a 7-year-old girl who received 18 mg daily of atomoxetine for the treatment of ADHD. Within hours of taking the first dose, the patient started talking nonstop and stated that she was happy. The next morning the child was still elated. Two hours after taking her second dose of atomoxetine, the patient started running very fast, stopped suddenly, and fell to the ground. The patient said she had “run into a wall” (there was no wall there). The reporting physician considered that the child was hallucinating. Atomoxetine was discontinued.

Have these people ever seen a child?

The methylphenidate prescribing information suggests an 0.1% risk of psychosis, which matches the other two studies pretty well.

Does stimulant psychosis always get better after the stimulant is discontinued? My strong impression is “yes”, but I am told that this study claims 5% to 15% of stimulant psychosis patients do not recover. I cannot find the full text to figure out exactly what they mean, and it looks like it was done on chronic meth addicts rather than prescription users.

So 0.1% – 0.2% of children who use prescription stimulants become psychotic (I predict less for adults), and 5-15% of those people stay psychotic after discontinuation (I predict this is about meth-heads and exaggerated). But worst case scenario, about 1/5,000 to 1/10,000 responsible stimulant users risks permanent stimulant-induced psychosis. I think this is very exaggerated, but can’t prove it.

Aggressive Behavior: This is just going to be the same as psychosis. Adderall isn’t going to magically turn gentle old grandmothers into killing machines. If you’re already a kind of violent guy, and you take a lot of Adderall, maybe it’ll push you over the edge.

Sudden Death: This is usually cardiovascular – something goes very wrong with your heart and it stops beating without warning. But UpToDate writes:

Reports of unexpected deaths of children receiving stimulant therapy have led to concerns that these medications increase the risk of cardiovascular (CV) adverse events, including sudden unexpected deaths (SUD) [1,2]. However, large cohort studies have not shown an increased risk of serious CV adverse events in children treated with stimulant therapy compared with the general pediatric population…

Among adult patients who are either current or new users of stimulant medications, there appears to be no increased risk of serious CV events. This was illustrated in a large retrospective cohort study of adults (age range 25 to 64 years) based on data from four large health plans that was done in parallel with the study performed in children discussed above [3,16]. Multivariant analysis demonstrated a lower risk of serious CV events (defined as myocardial infarction, stroke, and sudden cardiac death) in individuals who were current users of stimulant therapy versus nonusers (relative risk [RR] 0.83, 95% CI 0.72-0.96). In new users of ADHD medications compared with controls, the risk of serious CV events was even lower (RR 0.77, 95% CI 0.63-0.94). However, there may be a modest amount of healthy-user bias that favored the current users of stimulant therapy. To adjust for this potential bias, a multivariant analysis that compared current users with individuals who had used stimulant therapy more than one year ago (defined as remote use) found no difference in the risk of serious CV events (RR 1.03, 95% CI 0.86-1.24). The crude incidence of serious CV events in the overall cohort was 1.34 per 1000 person-years. These results showing no increased risk of serious CV events are consistent with previously discussed studies in pediatric patients.

And EUNETHYDIS:

when the number of patient-years of prescribed medication was incorporated into the evaluation, the frequency of reported sudden death per year of ADHD therapy with methylphenidate, atomoxetine or amfetamines among children was 0.2–0.5/100,000 patient-years [99]. The analysis of 10-year adverse-event reporting in Denmark resulted in no sudden deaths in children taking ADHD medications [5]. While it is recognised that adverse events are frequently under-reported in general, it is likely that sudden deaths in young individuals on relatively new medications may be better reported. Death rates per year of therapy, calculated using the adverse events reporting system (AERS) reports and prescription data, are equivalent for two ADHD drugs (dexamfetamine and methylphenidate): 0.6/100,000/year [37]. (The accuracy of these estimates is limited however, for instance because in moving from number of prescriptions to patient-year figures assumptions must be made about the length of each prescription). It seems likely, using these best available data, and assuming a 50% under-reporting rate, that the sudden death risk of children on ADHD medications is similar to that of children in general.

Despite this, I am always very wary prescribing stimulants to anyone with any history of heart problems. I always make these people go see a cardiologist. The cardiologist always says yeah, sure, whatever, but it makes me feel a lot better.

In General: Probably the most informative passage I’ve seen on the medical risks of stimulants is this one from Misuse Of Study Drugs:

In 1990, there were about 271 emergency room reports involving methylphenidate, 1,727 in 1998, and 1,478 in 2001 [32]. The total number of emergency department visits resulting from use of all psychotherapeutic CNS stimulants was 4091 in 1998, 3644 in 1999, 3336, in 2000, 3146 in 2001 and 3275 in 2002 [33]. There are approximately 25 emergency room deaths per year among up to 3 million users of prescription stimulant drugs (including both those medically prescribed and not prescribed these drugs). Thus, the likelihood of dying from such drugs appears to be approximately 1 in 120,000.

But isn’t 25 deaths per year still bad?

Here’s another passage from the same source:

Intravenous use of prescription stimulants is particularly dangerous. In particular, intravenous (IV) abuse of methylphenidate may result in talcosis. Talcosis is a reaction to talc, a filler and lubricant in methylphenidate and other oral medication. This inflammation reaction occurs in the lungs and related consequences include lower lobe panacinar emphysema.

People aren’t dying because their psychiatrist gave them Adderall 10 mg bid. They’re dying because they ground it up, injected it into their bloodstream, and had their lungs turn into talc. The people dying of stimulant use are doing things so horrifying you could not possibly imagine them even if you took ten times your prescribed dose of Adderall and used all of it to focus on writing a report on the most horrifying ways you could possibly use Adderall. Did you know that 13% of Massachusetts college students have ground up Ritalin and snorted it up their nose? Did you know the first case report of Ritalin abuse involved a patient who was taking 125 Ritalin pills daily? All of these people are out there, and still only 25 people die of stimulant-related causes per year!

My impression is that, in particularly at-risk people, stimulants may add +1/1000 to the risk of heart attacks per year, and +1/10,000 risk of long-term psychosis. Everything else in this category can be rounded down to zero.

III. Addiction

What about addiction risk?

The data on this are really poor because it’s hard to define addiction. If a prescription stimulant user uses their stimulants every day, and feels really good on them, and feels really upset if they can’t get them…well, that’s basically the expected outcome.

Wilens et al finds that over ten years, 10% of adolescents surveyed got high on their medication, and 22% sometimes used more than prescribed. Does that mean those 10% or 22% are “addicted”? Not really – some of them probably have a tough day one time, so they take two Adderall that day and no Adderall the day after. As for getting high – well, a lot of people get high on alcohol who aren’t alcoholics, and a lot of people get stoned who nobody would call addicted to marijuana.

A lot of studies in this area ask the kind of different question of whether children put on stimulants are more likely to be addicted to drugs in general as adults. Most of them find these children are less likely, which is hypothesized to be an effect of successfully treating their ADHD.

And there’s a book on narcolepsy which apparently claims that between less than 1% and 3% of people taking stimulants for that condition get addicted, but I can’t track down their methodology or really anything beyond one reference. And narcoleptics are a different population than ADHD patients and results might not generalize (though that number sounds kind of right).

I don’t think there are good data here, but my intuitions and personal experience is that “addiction” of the sort you get with heroin or tobacco is very rare, at least when responsible people without a personal or family history of addictive behavior take stimulants as prescribed. Most people agree the risk is lower for extended-release stimulants (eg Adderall XR), and very low for Vyvanse.

IV. Tolerance

Tolerance is when you keep needing more and more of a drug to get an effect. In the worst cases, your baseline changes so that you need the drug to feel normal. The concern is that long-term use of Adderall will make your attention naturally worse, so that medicated-you is only as good at concentrating as unmedicated-you was before, and unmedicated-you is even less attentive.

We know tolerance occurs over the short-term, and we encourage patients to take a few days off Adderall every week or two to let their bodies reset. More concerning is whether it happens over the space of years, where people’s bodies adjust in a more permanent way.

The best study of this phenomenon was the Multimodal Treatment of ADHD (MTA) study, which randomized children to be treated with stimulants or “behavioral therapy” (eg learning coping skills, etc). Behavioral therapy for ADHD is not very good and I interpret it as a nice way of saying placebo.

For the first year, the kids getting stimulants did much better on all metrics than behavioral-therapy-only. For the second year, they did a little better. By the third year, they were the same. In the eighth year, which was as long as anyone kept checking, they were still the same.

This is pretty concerning. It sounds like over three years people’s bodies built up some tolerance to stimulants, after which they provided no further benefit. The only saving grace is that there’s no evidence of stimulants ever making people worse than normal (even on people who stopped the medications later).

People have critiqued this study on the grounds that although they started off giving the experimental group stimulants vs. the control group behavioral therapy, any patient could switch treatments at any time and many of them did. By year three when the groups equalized, only 66% of the medication group was on medication, and a full 43% of the therapy-only group was. So maybe this just drowned out any original effect?

The authors of the study are not convinced:

It is tempting to conclude that intensive medication management beyond 14-months could have resulted in continued differences between the randomly assigned treatment groups…In a previous multimodal treatment study where medication was carefully titrated and monitored for two years, treatment gains were maintained for the entire period. However, after 14 months the MTA became an uncontrolled naturalistic follow-up study and inferences about potential advantages that might have occurred with continued long-term study-provided treatment are speculation. Moreover, with one exception (math achievement), children still taking medication by 6 and 8 years fared no better than their non-medicated counterparts despite a 41% increase in the average total daily dose, failing to support continued medication treatment as salutary (at least, continued medication treatment as monitored by community practitioners)…Finally, a previous analysis of the MTA data through 3 years did not provide evidence that subject selection biases towards medication use in the follow-up period accounted for the observed lack of differential treatment effects.

Thus, although the MTA data provided strong support for the acute reduction of symptoms with intensive medication management, these long-term follow-up data fail to provide support for long-term advantage of medication treatment beyond two years for the majority of children—at least as medication is monitored in community settings.

As far as I can tell, pretty much everyone has ignored this, using the usual range of meaningless excuses like “Well, treatment must be individualized to the patient”.

This is very tempting, because for example I have a lot of patients who have been on stimulants for decades, are still very excited about them, and think they’re doing great. Every so often these patients go off their stimulants, are very unhappy, and insist on going back on them again. They say that pre-stimulant, they were scatterbrained and always losing things and missing appointments and failing to do work, and now, after ten years of stimulant treatment, they feel great.

We can imagine ways these people are wrong. Maybe the stimulants worked for the first three years, stopped working so gradually they didn’t notice, and now they only notice the difference between being on stimulants (baseline), and immediate post-stimulant withdrawal (very bad). But this would require a lot of people to be really wrong about their internal experience.

I asked a question on the Slate Star Codex survey about this. People on Adderall more than one month were asked to tell me whether they had no tolerance problems, some tolerance requiring dose escalation, or high tolerance that made the medications stop working entirely. The preliminary results:

Adderall for between one month and one year: (n = 124)
62 (50%) No tolerance, worked as well as ever
57 (46%) Some tolerance, or required dose escalation, but still worked well in general
5 (4%) High tolerance, stopped working

Adderall for one to five years: (n = 117)
33 (28%) No tolerance, worked as well as ever
78 (67%) Some tolerance, or required dose escalation, but still worked well in general
6 (5%) High tolerance, stopped working

Adderall for more than five years: (n = 59)
23 (39%) No tolerance, worked as well as ever
33 (56%) Some tolerance, or required dose escalation, but still worked well in general
3 (5%) High tolerance, stopped working

All three categories were evenly divided between “no tolerance” and “some tolerance but still worked well”, with only about 5% saying the tolerance became a big problem. This matches my clinical experience. So either I’m right, or the problem where they get confused and forget their baseline is affecting my survey-takers.

There are occasional claims that magnesium or some other substance can help reverse Adderall tolerance. As far as I know these have never really been investigated.

So: there’s no good evidence that taking Adderall will actively make your ADHD worse in the long run. There is good evidence from clinical trials that benefits will decrease to zero over the space of a few years, apparently contradicted by the personal experiences of doctors and patients. Overall not sure what to do with this one.

V. Neurotoxicity

There’s some evidence that amphetamines can cause permanent cellular damage, but it’s not clear whether this happens in humans at typical therapeutic doses.

If you give rats very high doses of IV amphetamines, they accumulate so much dopamine in the cytoplasm of their neurons that it causes oxidative stress and destroys dopaminergic nerve terminals. This doesn’t happen to rats at doses matching human doses of Adderall. But it does happen at those doses to squirrel monkeys. At least this is the claim:

Adult baboons and squirrel monkeys were treated with a 3:1 mixture of D/L–amphetamine similar to the pharmaceutical Adderall for 4 weeks. Plasma concentrations of amphetamine (136±21 ng/ml-1) matched the levels reported in human ADHD patients after amphetamine treatment lasting 3 weeks (120–140 ng/ml-1) or 6 weeks in the highest dose (30 mg/day-1) condition (120 ng/ml-1). When the animals were killed 2 weeks after the 4-week amphetamine treatment period, both non-human primate species showed a 30–50% reduction in striatal dopamine, its major metabolite (dihydroxyphenylacetic acid (DOPAC)), its rate-limiting enzyme (tyrosine hydroxylase), its membrane transporter and its vesicular transporter. These consequences are similar, if not identical to the effects of neurotoxic doses in rodents.

I’m not really sure what they’re getting at here – surely they’re not saying just one month of Adderall permanently decreases striatal dopamine by 50%? But it sounds like something bad is happening, and since humans are more like monkeys than rats, maybe there’s cause for concern.

What would it look like if people got this kind of brain damage? One likely possibility is Parkinson’s disease, a condition caused by poor dopaminergic function in the brain. If you were going to tell a story about how Adderall could cause long-term neurotoxic damage, it would look like gradual decrease of brain dopaminergic function without obvious effects through most of the lifespan (since most people have dopaminergic function to spare). As the patient got older and started naturally losing brain function, Parkinson’s would appear. This happens to genetically and environmentally predisposed people anyway (which is why old people get Parkinson’s so often), but in this scenario amphetamine use would present an extra risk factor.

Several studies have shown that meth addicts do have higher rates of Parkinson’s disease. This one says people hospitalized for meth addiction are 60% more likely to get Parkinson’s than people hospitalized for other reasons. This one finds Parkinson’s rates three times higher in meth addicts compared to non-drug-users.

What about at therapeutic doses? This article claims there was a study that found people who used Benzedrine and Dexadrine (early forms of prescription amphetamine) in the 1960s have rates of Parkinson’s Disease about 60% higher than non-users today, but I can’t find the study itself and I don’t know the methodology. Another study finds similar results. Since both ADHD and stimulant addiction are very hereditary, you could make an argument that people who already have problems with their dopamine system are more likely to get Parkinson’s later on. There’s a little bit of conflicting evidence for this. Also, ADHD patients might have three times the rate of dementia with Lewy bodies, a condition closely related to Parkinson’s. On the other hand, there doesn’t seem to be any genetic connection. Overall my guess is this is not what’s going on.

About 1-2% of people will get Parkinson’s if they live long enough. If Adderall increases that risk 60%, then presumably it could cause a 1% absolute increase in risk.

Some people claim various substances (magnesium, minocycline, etc) will protect your brain from amphetamine neurotoxicity. None of these have been studied in anywhere near the depth they would need to be to make me feel comfortable with this.

The good news is that as far as anyone can tell, Ritalin doesn’t cause these problems, even if you give it to rats at super-high doses. It seems to be a difference in the mechanism of action. I’ve been talking about Adderall this whole post because it’s the most commonly-used stimulant and some studies have suggested it’s more effective for a few people, but this might be a strong argument in favor of starting with Ritalin and only switching to Adderall if Ritalin fails.

So overall there is plausible, but not incontrovertible, evidence linking Adderall to a somewhat increased risk of Parkinson’s disease in old age.

VI. Summary

My impression is that the risks of proper, medically supervised Adderall use are the following:

1. High risk of minor short-term side effects that might make you want to stop taking the medication with no long-term issues
2. Extremely low risk of serious medical side effects like stroke or heart attack, except maybe in a few very vulnerable populations
3. Maybe one percent risk, but not literally zero risk, of addiction if patients are well-targeted by their doctors and use the medication responsibly.
4. Around one in a thousand risk, but not literally zero risk, of psychosis. Some anecdotal evidence suggests it is more common than this. Most of these cases will be very mild. Some people find a very small number of cases of stimulant-induced psychosis may be permanent, though I still find this hard to believe.
5. Some evidence for tolerance after several years, though most patients will continue to believe it is helping them. No sign of supertolerance where it actually makes the condition worse.
6. Plausibly 60% increased relative risk (+~1% absolute risk) for Parkinson’s disease with long-term use; this is unlikely with Ritalin.
7. Unknown unknowns.

Of these, I find the tolerance and the Parkinson’s to be the most concerning. My most likely change after doing this research is to prescribe my patients who need stimulants Ritalin instead of Adderall. Most people find both stimulants work about equally well, and it seems potentially slightly safer. Given that the increased risk is only 1% in absolute terms, is still unclear, and may be incurred after only a few weeks of use, I’m not planning to force my patients who are currently happy on Adderall to switch to Ritalin right now.

I am pretty upset about the overall terrible state of this research. In particular, nobody except the MTA takes the possibility of tolerance seriously, and the MTA results really ought to have inspired a lot more soul-searching and hand-wringing than they actually did. The numbers on addiction are inexcusably terrible given how easy they would be to collect. Getting good data on the Parkinson’s risk would be harder, but one so-far-unexplored possibility would be to compare past prescription Adderall history to past prescription Ritalin history in Parkinson’s patients to adjust for the potential ADHD confounder. I really think somebody should do this.

Despite all this, I compare these risks to the risks of eating one extra strip of bacon per day and decide that overall this is not enough for me to stop prescribing stimulants to patients who I think might benefit from them. These are about the standard level of side effects for a powerful medication and I think there’s a major role for these in ADHD treatment as long as patients are well-informed about the risks they’re taking.

PS: I don’t accept blog readers as patients, and I won’t prescribe you Adderall just because you liked this post.

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nikolap
172 days ago
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StunGod
171 days ago
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As an adult who has been taking Adderall in one form or another for almost 20 years, I'm grateful for this article. I've pieced together some of this myself over the years, but this article is really a useful piece of info to share with an apprehensive primary care doctor or to make your own educated choices.
Portland, Oregon, USA, Earth

Why Cassini Is Ending Its Life with a Kamikaze Plunge - Facts So Romantic

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“‘Are we alone? ‘Is there other life in the solar system?’ We want the real answer, not the ‘oops’ answer.”Photograph by ESA/ISS038 / Stuart Rankin / Flickr

This Friday, NASA’s Cassini probe will run out of fuel and take pictures as it plummets at 75,000 miles per hour through Saturn’s atmosphere. It won’t be crashing—the heat from friction will make Cassini immolate in the sky.

Cassini has had a good run. Since arriving at Saturn in 2004, the probe has transmitted stunning images of the ringed planet, including its uncanny hexagonal storm, and of its many moons. It found the largest, Titan, harboring methane oceans and icy Enceladus venting water-rich plumes from over 100 so-far identified geysers; the latter might bear ocean life beneath its miles-thick ice cover. Cassini’s dive towards Saturn’s surface will present scientists with a never-before-seen perspective of the planet, along with its atmosphere and magnetic fields, and data on Saturn’s rings’ age and make-up.

It’s the possibility of contaminating Saturn’s moons, though, that is the more interesting motivation for what NASA has been calling Cassini’s “Grand Finale.” “Whenever NASA plans any missions, they always include plans for what we call spacecraft disposal,” said Morgan Cable,…
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nikolap
271 days ago
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Brief Cautionary Notes On Branded Combination Nootropics

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I.

Taking nootropics is an inherently questionable decision. The risk isn’t zero, and the benefits are usually subtle at best.

On the other hand, mountain-climbing also has risks, and is so devoid of benefit that the only excuse mountaineers can come up with is “because it’s there”. So whatever. If someone wants to do either – well, it’s a free country, and we all have to amuse ourselves somehow.

But even within this context, special caution is warranted for branded combination nootropics.

I wanted to make up a caricatured fake name for these sorts of things, so I could make fun of them without pointing at any company in particular. But all of the caricatured fake names I can think of turn out to be real products. MegaMind? Real. SuperBrain? Real. UltraBrain? Real. Mr. Power Brain? Real, for some reason.

Even the ones that don’t make sense are real. NeuroBrain? Real, even though one hopes that brains are always at least a little neuro. NeuroMind? Real, with its own Indiegogo campaign. The only thing I haven’t been able to find is a nootropic called BrainMind, but it’s only a matter of time.

These usually combine ten or twenty different chemicals with potential nootropic properties, then make outrageous claims about the results. For example, Neuroxium says on its ridiculous webpage that:

Neuroxium is a revolutionary brain supplement formulated to give you ultimate brain power. Known in Scientific Terms as a “NOOTROPIC” or “GENIUS PILL” Neuroxium improves mental functions such as cognition, memory, intelligence, motivation, attention, concentration and therefore happiness and success.

Your first warning sign should have been when they said “genius pill” was a scientific term (or as they call it, Scientific Term). If you needed more warning signs, this is word-for-word the same claim made by several other nootropics like Synagen IQ, Nootrox, and Cerebral X. So either they can’t even be bothered not to plagiarize their ads, or they change their name about once a week to stay ahead of the law.

I was eventually able to find a list of the ingredients in this stuff:

DMAE (dimethylethanolamine bitartrate), GABA (?-Amino-butyric acid), Caffeine anhydrous, Bacopa monnieri leaf extract, NALT (N-acetyl-L-tyrosine), Centrophenoxine HCl, Alpha-GPC (a-glycerophosphocholine, Agmatine sulfate, Gingko biloba leaf extract, Pine (Pinus pinaster) bark extract, Phosphatidylserine, Aniracetam, CDC Choline (Citicoline), Sarcosine (N-methylglycine), Vincamine [Lesser Periwinkle (Vinca minor) aerial extract], L-Theanine (?-glutamylethylamide), NADH (nicotinamide adenine dinucleotide), TAU (triacetyluridine), Noopept, Adrafinil, Tianeptine, Piperine [Black Pepper (Piper nigrum) fruit extract 445mg.

And the weird thing is, a lot of these are decent choices. Everyone knows caffeine is a good stimulant. Adrafinil is the over-the-counter version of modafinil, an FDA-approved medication for sleep disorders; many of my patients have been very happy with it. Bacopa monnieri has been found to improve memory in so many studies I can’t even keep track of all of them. Noopept is an approved medication in Russia. Tianeptine is an approved medication in France. All of these are chemicals with at least some evidence base behind them, which are potentially good for certain people. If some nootropics user were to say they wanted to try adrafinil, or bacopa, or noopept, or any of the other stuff on that list, I would classify them with the mountain climber – doing something risky but not necessarily stupid.

But taking Neuroxium/Synagen/CerebralX is exactly as bad an idea as you would expect from the advertising copy.

For one thing, they don’t list the doses of any of these things – but they have to be getting them terribly wrong. A standard dose of adrafinil is 600 mg. A standard dose of bacopa is 300 mg. A standard dose of Alpha-GPC choline is about 600 mg. So combining standard doses of just these three ingredients means you need a 1.5 g pill. This is probably too big to swallow. The only pills I know of that get that big are those gigantic fish oil pills made of pure fish oil that everybody hates because they’re uncomfortably big. But this is just what you’d need to have three of the 22 ingredients listed in CerebralX at full doses. The pill is already unswallowably large, and you’ve only gotten a seventh of the way through the ingredient list.

I conclude that they’re just putting miniscule, irrelevant doses into this so they can say they’ve got exciting-sounding chemicals.

For another thing, all of these substances have unique profiles which have to be respected on their own terms. For example, lots of studies say bacopa improves memory – but only after you’ve taken it consistently for several months. If you just go “WOOO, CEREBRALX!” and swallow a bunch of pills and hope that you’ll do better on your test tomorrow, all you’re going to get are the short-term effects of bacopa – which include lethargy and amotivation.

Most sources discussing Noopept recommend starting very low – maybe as low as 5 mg – and then gradually increasing to a standard dose of 10 – 40 mg depending on how it works for you. Some people will apparently need higher doses, and some find it works best for them as high as 100 mg. Needless to say, none of this is possible if you’re taking CerebralX. You’ll take whatever dose is in the product – which they don’t tell you, and which is probably so low as to be meaningless – and stay at the same level for however long you’re taking the entire monstrosity.

Tianeptine has a short half-life and is typically dosed three times a day, unlike most of the other things on the list which are dosed once per day. CerebralX says you should take their whole abomination once a day, which means you’re getting the wrong dosing schedule of tianeptine.

GABA, taken orally, doesn’t cross the blood-brain barrier and has no effect. The only way it could possibly make a difference – and even this is debatable – is if you join it to niacin to create the N-nicotinoyl-GABA molecule, which these people did not do. As a result, their GABA will be totally inert. This is probably for the best, because most of the things on their list are stimulants, and GABA is a depressant, so it would probably all just cancel out.

Piperine is a chemical usually used to inhibit normal drug-metabolizing enzymes and enhance the effect of other substances. This is very occasionally a good idea, when you know exactly what drug you’re trying to enhance and you’re not taking anything else concurrently. But I can’t figure out which drug they’re trying to enhance the activity of here, or even whether they’re trying to enhance the activity of anything at all, or if they just heard that piperine could enhance things and thought “Okay, it’s in”. And if I were giving someone a concoction of twenty-one different random psychoactive drugs, which I was dosing wrong and giving at the wrong schedule, the last thing I would want to do is inhibit the body’s normal drug metabolism. The entire reason God gave people drug-metabolizing enzymes is because He knew, in His wisdom, that some of them were going to be idiots who would take a concoction of twenty-one different random psychoactive drugs because a website said it was, in Scientific Terms, a “GENIUS PILL”. Turning them off is a terrible idea and the only saving grace is that the dose of everything in this monstrosity is probably too small for it to do anything anyway.

Taking any of the ingredients in CerebralX on its own is a potentially risky affair. But if you study up on it and make sure to take it correctly, then maybe it’s a calculated risk, like mountain climbing. Taking everything in CerebralX together is more like trying to mountain-climb in a t-shirt and sandals. You’re not taking a calculated risk as part of a potentially interesting hobby. You’re just being an idiot.

II.

But that’s too easy. I have a larger point here, which is that these sorts of branded combos are bad ideas even if they’re by smart, well-intentioned people who are doing everything right.

Tru-Brain is undeniably in a class above CerebralX. It has a team including neuroscience PhDs. It seems to be a real company that can keep the same name for more than a week. Instead of promising a GENIUS PILL, it makes comparatively modest claims to be able to “perform at your peak” and “stay sharp all day long”.

Correspondingly, its special nootropics combo makes a lot more pharmacological sense. For one thing, it’s a packet rather than a single pill – a concession to the impossibility of combining correct doses of many substances into a single capsule. For another, it limits itself to mostly things that some sane person could conceivably in some universe want to dose on the schedule they recommend. And it’s only got seven ingredients, none of which counteract any of the others or turn off important metabolic systems that God created to protect you from your own stupidity. This is probably about as well-designed a branded nootropics combo as it’s possible to make.

But I would still caution people away from it. Why?

Last year, I surveyed people’s reactions to various nootropics. I got 870 responses total, slightly fewer for each individual substance. Here are the response curves for two of the substances in TruBrain – piracetam and theanine:

These are on a 1-10 scale, where I directed responders to:

Please rate your subjective experience on a scale of 0 to 10. 0 means a substance was totally useless, or had so many side effects you couldn’t continue taking it. 1 – 4 means for subtle effects, maybe placebo but still useful. 5 – 9 means strong effects, definitely not placebo. 10 means life-changing.

Some substances known to be pretty inert averaged scores of around 4. Piracetam and theanine averaged around 5, so maybe a little better than that. But the most dramatic finding was the range. Almost 20% of people rated theanine a two or lower; almost 20% rated it a nine or higher. More than a third placed it in the “probably placebo” range, but 5% found its effects “life-changing”.

The effect of nootropics seems to vary widely among different people. This shouldn’t be surprising: so do the effects of real drugs. Gueorguieva and Mallinckrodt do an unusually thorough job modeling differences in response to the antidepressant duloxetine, and find a clear dichotomy between responders and nonresponders. This matches psychiatric lore – some medications work on some people, other medications work on others. I particularly remember one depressed patient who had no response at all to any SSRI, but whose depression shut off almost like a lightswitch once we tried bupropion. Other people fail bupropion treatment but do well on SSRIs. Probably this has something to do with underlying differences in their condition or metabolism that we just don’t know how to identify at this point (sample simplified toy model: what we call “depression” is actually two diseases with identical symptoms, one of which responds to SSRIs and one of which responds to bupropion).

I think this is why there are no multidrug combo packs. Your psychiatrist never treats your depression with a pill called “MegaMood”, boasting combination doses of Prozac, Wellbutrin, Remeron, and Desyrel. For one thing, either you’re giving an insufficient dose of each drug, or you’re giving full doses of four different drugs – neither is well-tested or advisable. For another, you’re getting four times the side effect risk. For a third thing, if one of the four drugs gives you a side effect, you’ve got to throw out the whole combo. For a fourth, if the combo happens to work, you don’t know whether it’s only one of the four drugs working and the others are just giving you side effects and making you worse. And if it sort of works, you don’t know which of the four drugs to increase, or else you just have to increase all four at once and hope for the best.

All these considerations are even stronger with nootropics. There shouldn’t be universally effective nootropics, for the same reason there’s no chemical you can pour on your computer to double its processing speed: evolution put a lot of work into making your brain as good as possible, and it would be silly if some random molecule could make it much better. Sure, there are exceptions – I think stimulants get a pass because evolution never expected people to have to pay attention to stimuli as boring as the modern world provides us with all the time – but in general the law holds. If you find a drug does significantly help you, it’s probably because your brain is broken in some particular idiosyncratic way (cf. mutational load), the same way you can double a computer’s processing speed with duct tape if one of the processors was broken.

If everyone’s brain is broken in a different way, then not only will no drug be universally effective, but drugs with positive effects for some people are likely to have negative effects for others. If (to oversimplify) your particular brain problem is not having enough serotonin, a serotonin agonist might help you. But by the same token, if you have too much serotonin, a serotonin agonist will make your life worse. Even if you have normal serotonin, maybe the serotonin agonist will push you out of the normal range and screw things up.

Most effective psychiatric drugs hurt some people. I mean, a lot of them hurt the people they’re supposed to be used for – even the psychotic people hate antipsychotics – but once you’ve brushed those aside, there are a lot of others that help a lot of people, but make other people feel worse. There are hordes of people who feel tired on stimulants, or sleepy on caffeine, or suicidal on antidepressants, or any other crazy thing. You rarely hear about these, because usually if someone’s taking a drug and it makes them feel worse, they stop. But psychiatrists hear about it all the time. “That antidepressant you gave me just made me feel awful!” Oh, well, try a different one. “That’s it? Try a different one? Aren’t you embarassed that your so-called antidepressant made me more depressed?” You’re pretty new to this ‘psychopharmacology’ thing, aren’t you?

Thus the tactic used by every good psychiatrist: try a patient on a drug that you think might work, make them report back to you on whether it does. If so, keep it; if not, switch.

If you take a seven-drug combo pack, you lose this opportunity for experiment. Suppose that two of the drugs make you feel +1 unit better, two others have no effect, and three of the drugs make you feel -0.5 units worse, so in the end you feel +0.5 units better. Maybe that seems good to you so you keep taking it. Now you’re taking five more drugs than you need to, including three making you actively worse, and you’re missing the chance to be a full +2 units better by just taking the drugs that are helping and not hurting.

You’re also missing the opportunity to play with the doses or the schedules of things. Maybe if you doubled the dose of one of the drugs making you +1 better, you could be +2 better, but if you double the dose of the other, you start getting side effects and the drug only breaks even. If you experiment, you can figure this out and take twice the dose of the first and the starting dose of the second, for +3 better. Taking them all as part of a combo ruins this: if you try taking twice the dose of the combo, nothing happens.

(And a special word of warning: if some stimulant product combines caffeine with something else, and you feel an effect, your first theory should be that the effect is 100% caffeine – unless the “something else” is amphetamine. There are like a million products which bill themselves as “organic energy cocktails” by combining caffeine with some rare herb from Burma. People drink these and say “Oh, this high feels so much more intense than just drinking caffeine”. Yeah, that’s because it’s much more caffeine. Seriously. Check the doses on those things. I will grudgingly make an exception for some chemicals that are supposed to decrease caffeine jitters, like theanine, which might have a real effect. But the stimulation is from caffeine. Go get an espresso instead.)

III.

But don’t drugs interact? Instead of viewing these seven drugs as seven different variables, shouldn’t we view them as coming together in a seven-color beautiful rainbow of happiness, or whatever?

Once again, I can only appeal to psychiatry, which is still unsure whether there are any useful interactions between its various super-well-studied drugs which it’s been using for decades and prescribing to millions of people. Take the CO-MED study, which combined the popular SSRI escitalopram with the popular NDRI bupropion. Since depression seems to involve abnormalities in the three major catecholamine systems, and escitalopram hits one of these and bupropion hits the other two, this seems like exactly the sort of synergistic interaction we should expect to work. It doesn’t. CO-MED found that the two antidepressants together didn’t treat depression any better than either one alone, let alone produce some synergy that made them more than the sum of their parts. They did, however, have about twice as many side effects.

Other smaller studies say the opposite, so I’m not saying never try escitalopram and bupropion together. I’m saying we don’t know. These are intensely-studied drugs, the whole power of the existing system has been focused on the question of whether they synergize or antisynergize or what, and we’re still not sure.

Also from psychiatry: we know a lot less about the mechanisms of action of drugs than we like to think. Ketamine has been intensively studied for depression for a decade or so, and we only just learned last year that it probably worked on a different receptor than we thought. SSRIs might be the most carefully studied drug class of all time, and we still don’t really know exactly what’s up with them – it can’t just be serotonin; they increase serotonin within a day of ingestion, but take a month to work.

So when people take these incredibly weird substances that have barely been studied at all, where we have only the faintest clue how they work, and then say from their armchair “And therefore, drug A will enhance the effects of drug B and C” – this is more than a little arrogant. Is it all made up? I can’t say “all” with surety. But it might be.

The best-known and most-discussed interaction in nootropics is piracetam-choline. Piracetam increases levels of acetylcholine, which is formed from choline, so it makes sense that these two substances would go well together. Most sites on piracetam urge you to take them together. TruBrain, which predictably is on top of this kind of stuff, combines them together in its combo pack.

But there’s never been a human study showing that this helps. Examine.com, another group which is usually on top of stuff, summarizes (emphasis carried over from original):

[Choline] may augment the relatively poor memory enhancing effects of Piracetam in otherwise healthy animals, but administration of choline alongside Piracetam is not a prerequisite to its efficacy and has not been tested in humans

I surveyed a bunch of choline users, using a little gimmick. Some of the forms of choline sold these days don’t cross the blood-brain barrier and shouldn’t have an effect, so they provide a sort of placebo control for more active forms of choline. In my survey, people who took piracetam with inactive forms of choline didn’t report any worse an experience than those who took the real thing.

This is the most famous and best-discussed interaction in the entire field of nootropics, and it’s on super-shaky ground. So trust me, the CerebralX people don’t have good evidence about the interactions of all twenty-one of their ridiculous substances.

I have to admit, I’m not confident in this part. Maybe psychiatry is wrong. Sometimes I wonder what would happen if we just throw five different antidepressants with five different mechanisms of action at somebody at once. Realistically, maybe this would involve some supplements: l-methylfolate, SAMe, tryptophan, turmeric, and a traditional SSRI. One day I want to try this on someone I know well enough to let me test things on them, but not so well I don’t mind losing a friend when it all blows up in my face. Until then, keep in mind that anyone who says they bet a certain combination of things will produce a synergistic interaction is engaging in the wildest sort of speculation.

IV.

One more piece of evidence. The 2016 nootropics survey asked people to rate their experiences with 35 different individual substances, plus a branded combo pack (“AlphaBrain”) of pretty good reputation. The AlphaBrain performed worse than any of the individual substances, including substances that were part of AlphaBrain!

This is of course a very weak result – it wasn’t blinded, and maybe the survey responders have the same anti-branded-combo prejudice I do. But it at least suggests knowledgeable people in the nootropics community are really uncomfortable with this stuff.

90% of the people making branded combo nootropics are lying scum. A few, like TruBrain, seem like probably decent people trying to get it right – but are you confident you can tell them apart? And if you do manage to beat the odds and get something that’s not a complete pharmacological mess, aren’t you still just going to end up with an overpriced bundle of black boxes that won’t provide you with useful information, and which, empirically, everyone hates?

If you’re interested in nootropics, consider trying one substance at a time, very carefully, using something like examine.com to learn how to take it and what the possible side effects are. If you can, do what people like Gwern do and try it blind, mixing real pills with placebo pills over the space of a few weeks, so you can make sure it’s a real effect. If you find something that does have a real effect on you, treat that knowledge as a hard-won victory. Then, if you want to go from there, tentatively add a second chemical and test that one in the same way. Do this, and you have some small sliver of a chance of doing more good than harm, at least in the short term.

But if you’re going to order a combination of twenty different things at homeopathic doses from somebody who thinks “GENIUS PILL” is a Scientific Term – well, I hope it works, because you need it.

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nikolap
301 days ago
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Is Amazon's AWS Hiring 'Demolishing The Cult Of Youth'?

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Tech analyst James Governor argues that Amazon's cloud business is "demolishing the cult of youth." It just announced it is hiring James Gosling, one of the original inventors of Java... Meanwhile James Hamilton continues to completely kick ass in compute, network, and data center design for AWS... He's in his 50s. Tim Bray, one of the inventors of XML, joined Amazon in 2014. He's another Sun alumni. He's 61 now. He still codes. When you sit down with one of the AWS engineering teams you're sitting down with grownups... Adrian Cockcroft joined AWS in October 2016. He graduated in 1982, not 2002. He is VP Cloud Architecture Strategy at AWS, a perfect role for someone that helped drive Netflix's transition from on-prem Java hairball to serious cloud leadership. Great engineering is not maths -- it involves tradeoffs, wisdom and experience... The company puts such a premium on independent groups working fast and making their own decisions it requires a particular skillset, which generally involves a great deal of field experience. A related trend is hiring seasoned marketing talent from the likes of IBM. Some other older companies have older distinguished engineers because they grew up with the company. AWS is explicitly bringing that experience in. It's refreshing to the see a different perspective on value. In a later post the analyst acknowledges engineering managers are generally older than their reports, but adds that "If AWS sees value in hiring engineering leadership from folks that are frankly a bit older than the norm in the industry, isn't that worth shining a light on?" In response to the article, XML inventor Tim Bray suggested a new acronym: GaaS. "Geezers as a service," while Amazon CTO Werner Vogels tweeted "There is no compression algorithm for experience."

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nikolap
383 days ago
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Poly Styrene Is the Punk Icon Who Deserves Your Respect

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Once you hear Poly Styrene's high pitched, opera-trained warrior shout exclaiming "OH BONDAGE UP YOURS!" on the tail of a sweetly uttered "some people think little girls should be seen and not heard" you're immediately moved by the legendary X-Ray Spex frontwoman. Poly Styrene may have been a small, braces-wearing teenager, but nobody was gonna shut her up, even before she achieved punk icon status. No way in hell.

When I first heard X-Ray Spex, Poly's voice cut right through my disheveled pile of teen-angst and cheap thrift store clothes and shook me to the core. It was the 90's and I was just getting into punk and listening to a lot of cassette tape mixes generously bestowed upon me by my much cooler and more informed friends. I couldn't help but notice how much Poly Styrene's voice reminded me of other punk girls I was getting into at the time, like Kathleen Hanna and Corin Tucker, to name a few. It didn't dawn on me at the time that this voice had come 20 years before the others and why that was significant.

Now, more than two decades later (I'm old now, but who cares) and this obscenely sexist, racist, and idiotic era in our political history seems like the perfect time for a Poly Styrene revival. That's why the crowdfunding efforts for I AM A CLICHÉ, a documentary about Poly co-written and narrated by her daughter Celeste Bell, feel especially prescient. Germ Free Adolescents, the one and only X-Ray Spex album, turns 40 next year and the film is set to be released in time to celebrate.

If you're not familiar with the album or Poly Styrene herself, welcome. It is, as the saying goes, better late than never. While the Sex Pistols were being produced/manufactured by a fetish-wear shop owner/marketing genius (Malcolm Mclaren and Vivienne Westwood's shop was literally called SEX and sold bondage gear among other items), a young Poly Styrene was obsessed with dayglo and plastics, the idea of rebelling against cheap consumerism, and not being (literally) tied down by the man. After seeing an early performance of the Sex Pistols on Hastings Pier on July 3, 1976 (her 19th birthday), Poly—whose real name was Marian Elliot-Said—thought that if those guys could make music, she could too. So she picked her new name from the yellow pages and placed ads in NME and Melody Maker with the header YOUNG PUNX WHO WANT TO STICK IT TOGETHER.

The young girl with a mouth full of braces who had run away from home at 15 to tour the English countryside christened herself Poly Styrene, a cheeky name chosen for being lightweight disposable plastic, and she was about to take the London punk scene by storm. Once she formed the band, the X-Ray Spex played their debut at London's Roxy after only six rehearsals. They quickly gained popularity with Poly's voice and completely unconventional look making a huge impression.

When I started getting into Poly's music in the pre-YouTube years, so I wasn't able to see all the incredible video footage of X-Ray Spex that's out there today. If I had, I probably would've mimicked Poly by rocking pastel, dayglo colors, and crazy headbands, instead of trying to be grunge, and I definitely would have been way less ashamed of my braces and curly hair. And seeing a young woman of color fronting one of the most famous bands in the early punk scene would have been beyond inspiring.

According to Celeste, much was made about Poly's mixed parentage in the tabloids after she became famous. Poly's mom Joanne was white and her dad was a dispossessed Somali aristocrat. Many assumed that the song "Identity" was about race when in fact it was inspired by Poly witnessing a girl attempting suicide in a club toilet. Similar to all the Brexit nonsense of today, England back in the 70's was full of racism and anti-immigrant sentiment. But Poly rose above the prejudice and defied stereotypes, having once said , "I've always been happy, and well, rather intrigued, by a family tree that includes Spanish Princes, Celts, Imams, Ancient Bretons, and Somaliland tribal chiefs that descend from Abraham and Sarah."

People also tried to make a big deal about where Poly grew up. They tried to paint a picture of Poly's supposedly rough childhood living a tenement in South London's ethnically diverse and low-income Brixton district, but Poly wasn't having it. "Mum was forced to leave Bromley because she felt it was too white and judgemental for me to grow up in and that we could never be accepted. That's why we moved to Brixton. But although life was a bit austere, we were always well fed, clean and respectable—mum was a legal secretary, and where we lived that was considered posh!"

Poly refused to be put into a box or labeled by people trying to sell her story. She was a totally different person when she wasn't on stage. As exemplified by this amazing Australian TV interview from 1977, Poly was rather soft spoken and not at all eager to put on a front for journalists.

Similarly, a piece following her around for BBC4 shows a mild-mannered, contemplative Poly gently navigating the London streets and getting ready for shows.

Poly really exploded out of her shell on stage. It's almost as if that voice had to come out somehow and Poly's body was just a vessel. And Poly was not about to dress up that vessel or package herself or play into anyone's notion of femininity. "I said that I wasn't a sex symbol and that if anybody tried to make me one I'd shave my head tomorrow," Poly declared in a particularly candid interview for NME in May of '78. Interestingly enough, she ended up shaving her head at Johnny Rotten's flat a few weeks later.

In this same interview, Poly talks about moving back to the country with her mom and sister after feeling utterly sucked dry. "You feel all the time that people are draining you, draining off your energy all the time until you think, 'Blimey, I haven't got anything left to give. Leave me alone.'" The Spex had just returned from NYC from a two week residence at CBGB where they played twice a night. All of Poly's playful visions of a plastic world had become too real. "For them it wasn't a joke, it was the way they lived for real. For me it was all a joke: play with it, indulge it, have fun with it because there's not really that much of it over here. But when you go there it's so bad that you think, 'God, if that's what it's going to be like I don't want it.'"

America's ultra plastic society as embodied by NYC in the late 70's and the energy vampires of London's Chelsea neighborhood were starting to bring Poly down. And this was before Germ Free Adolescents had even dropped. Poly's ability to put up a front and endure the challenges of fame was coming to an end.

When I ask Celeste about why the Spex only put out one album she replied: "My mother had a big mental breakdown when X-Ray Spex were at the height of their success. This was the main reason—it had all become a bit much for my mum and she wanted to do something more lowkey." Poly had also realized that she had bipolar disorder.

Celeste adds: "She always felt different from other people since she was a kid and had real problems concentrating at school and she had big anger management issues—she was always getting into fights and her moods fluctuated a lot. So she was aware something was not quite right from a young age. But it was not until she was 19/20 that it was apparent she was suffering from a full blown mental illness."

In a parallel to the explosion and quick death of the early punk scene in the UK, Poly was a bright burning flame that had no choice but to extinguish itself. But luckily Poly's spark remained intact. Before her 2011 death at the age of 53 to breast cancer, Poly put out two more albums—the moody, mellow, post-punk Translucence just after she left X-Ray Spex and the spunky, socially conscious Generation Indigo, which she released and promoted just prior to her death.

Up to the end, Poly stayed optimistic about the world and life itself like a true warrior. She told a reporter from the Guardian on her deathbed: "I try not to be negative or cynical. Even though we're in a crazy situation, economically, and with wars, when things go far right, they will have to swing left. We have to become more caring and sharing. Generation Indigo are the people who will protest peacefully, and it's happening already."

She's also quoted as saying ""You remember that old song 'Que Sera Sera, Whatever will be, will be, the future's not ours to see'? I've always felt that. It's been a roller coaster ride, but I wouldn't change a thing."

Lucky for us, Poly's roller coaster ride is getting the cinematic treatment it so deserves. "I think in the documentary you will see that my mother was, apart from being an amazing performer and singer/songwriter she was also a true artist and visionary years ahead of her time," notes Celeste. I can't wait to see the film.

Check out the Indiegogo page for Poly Styrene: I Am A Cliché here.

Rachel Fernandes is a writer, film producer, and programmer living in Southern California. Follow her on Instagram.



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Here's How to Recreate the Smart-as-Hell Sampling from Kendrick's "LOYALTY."

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"Ugh, rappers just steal other people's songs! Why don't they learn to play some instruments?" So says your terrible rockist friend (and at this point, why are you still friends with them?). Never mind that most beats nowadays are original compositions by musicians with strong ears for melody, harmony, and rhythm, but the older art of sampling itself is loaded with hidden meaning and careful craft. Case in point: Kendrick Lamar's summer jam contender "LOYALTY."

The track's notable for many other reasons—among them being Rihanna's guest turn as a rapper, not a hook singer—but maybe most intriguing is the funhouse mirror flip of Bruno Mars' "24K Magic" by producers DJ Dahi, Sounwave, and Terrace Martin. The loop is so warped and diced that it's nigh-unrecognizable on first listen, but as this unofficial but educational video from a YouTube producer shows, it's not all that complicated, just very clever. Reversing the intro, then pitching it up a few semitones is a cinch, but it's the microhouse-styled chops that really impress. Unfortunately, if you're like me, you'll only be able to notice these tricks and not enjoy the flawless rapping happening on top. Such is the price of knowledge. Watch the video breakdown of Kendrick's "LOYALTY." below.

Phil is a Mac scrub so he's never used FL. He's on Twitter.



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