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Hi I’m Rose Rimler filling in for Wendy Zukerman this week because she’s busy competing in a 24-hour dance marathon. She’ll be back next season. This is Science Vs from Gimlet, the show that pits facts against focus. Today on the show– Adderall. That’s a drug that is often used to treat[1] attention deficit hyperactivity disorder, or ADHD[2]. You may have heard that this drug is in short supply right now in the US[3][4]..

<<The Food and Drug Administration is now confirming a nationwide shortage of Adderall>>

<<More than 6 in 10 pharmacies are reporting difficulties in obtaining Adderall medication[5]>>

<<I just had to call 10 different pharmacies to find one to find my ADHD meds in stock. >>

There are several different companies that make versions of Adderall. One company has said the shortage is basically caused by a combination of not enough workers[6][7] and too much demand[8]. It became easier to get prescriptions during the pandemic, because you could do it online from some telehealth companies.[9] But even before the pandemic, demand was going way up[10][11]. So more and more people are on this stuff.[12][13][14][15] And this has been freaking some people out[16]… because of claims about what Adderall is…

<<A derivative of Meth, a highly addictive drug.>>

<<The scary part? It’s made of amphetamine>>

<<They give you adderall, which is fu**ing speed!>>

Yeah, Adderall is amphetamine[17]. A stimulant[18][19]. Lots of illegal.[20] drugs are stimulants too– like cocaine[21] and methamphetamine. In fact, Adderall is in the same family as meth. And in some countries, Adderall is illegal– like Japan[22] and Sweden[23]. 

So, today on the show, we’re asking:

  1. What can Adderall do for someone who has ADHD?
  2. What if you don’t have ADHD. Can Adderall boost your brain?  and
  3. Is it dangerous to put people on this drug that’s in the same category as meth?

Because when it comes to Adderall, there’s NO shortage…of opinions. But then, there’s science.

Science Vs Adderall is coming up after the break.


PREROLL BREAK

Welcome back. Today we’re focusing on Adderall. It’s typically prescribed to people who have ADHD. This is where people have so much trouble paying attention or sitting still or both– that it really is a big problem in their life[24]. Scientists used to think ADHD was a childhood thing[25][26]– but more and more people are getting diagnosed as adults[27][28]. It’s estimated that about 3% of adults around the world have ADHD[29]. And a lot of them say that being on Adderall is a game changer. So what does that look like?

BEAT 1 KAI

To dive in, let’s talk to Kai Liu…. she’s an actor,[30] writer, artist, and pug mom.

KL I have 3 rescue dogs currently.

RR That’s a lot of dogs

KL You know you get one dog and then the other dog needs a friend and then that dog needs a friend and pretty soon you’re just drowning in pugs.

Kai told us what it was like before she got treated for her ADHD.

 

KL I would space out a lot, I would dissociate, which presented itself to others as just kind of daydreamy, not really super smart. I just thought I was a very space cadet kind of person.

But Kai didn’t know that this was ADHD until her late 20s. It came to a head during a rough patch she was going through. She was getting work as an actor… shooting commercials, but it wasn’t going well.

KL I would just be so distracted that I wouldn't be able to hear the other performers feeding me lines. I wouldn’t be able to take direction very well from the director, which is not a good thing as an actor.

Sitting down to learn her lines was giving her panic attacks. She couldn’t memorize scripts. Which meant she was botching auditions. Then one night, she had an epiphany. She was at a bar with some friends. Everything was distracting her– the chatter inside the bar, the dogs on the sidewalk, the people coming and going. Suddenly, her friend leaned over and said…

KL Kai are you OK? You seem really frazzled. And my first instinct was just to recoil and take offense to that. Because why would you point that out, that's so mean. I'm not frazzled, you're frazzled. But then I realized I didn't know other people could see that I was frazzled all the time. I thought it was internal and I was masking it really well. And that's when I realized I might have a problem.

Soon after that, Kai got diagnosed with ADHD by her doctor. And they decided she should try Adderall. Kai filled the prescription, and took the bottle home. 

KL I read the label and I saw it was an amphetamine and I was like, oh, what a fun day this is gonna be. It can either be real good or real crazy. Luckily, it was real good.

Within an hour of taking her first pill, Kai could feel a change come over her…she had no trouble focusing on what she wanted or needed to do.

RR Do you remember the moment you felt it started to kick in?

KL Yeah it was it was like clouds parting in my head so that i could see sunlight

RR wow!

KL I couldn't believe this is how people without ADHD functioned on a daily basis, I was just so surprised, I even went to my husband and said is this how you live every day? You can get so many things done! He basically looked at me and went, yeah, it is. To which I was like, why don't you do more things around the house then 

RR laugh

KL But y’know those are daily marriage struggles

RR uh huh laugh

BEAT 2 Rachel

So, what happened here? What is going on in the brains of people like Kai who have ADHD - and how does Adderall show some people the light? To find out, we called up Rachel Fargason, a professor and psychiatrist at the University of Alabama at Birmingham[31].

RF You happened to hit upon probably my favorite subject in the world.

Rachel has been treating people with ADHD for years. Here’s how she explains what ADHD is like–

RF You know when you have a list of 10 things to do, you check each one off, you run your errands and that feels so good?

RR Yeah

RF So simple things tend to make most people happy, but people with ADHD need a little more stimulation to make them happy. It just feels so boring, so hard for them to do, it’s like pulling teeth.

They’re not getting that pat on the back from the brain that this thing they’re doing? Is worth it.

Scientists can actually SEE this when they scan the brains of people with ADHD. For example, in this one study, scientists brought 29 people into the lab: about half had untreated ADHD and half did not have ADHD[32]. Then, they scanned their brains while they showed them pictures of money, and told them that they’d get some real money for every picture of money they saw.[33] Then, the scientists tried a different thing– they tried showing people a symbol: a grey diamond BEFORE the picture of the money. For people without ADHD, a part of their brain in the reward system started lighting up when they saw that grey diamond. They knew that a reward was probably coming. But in the brains of people with ADHD, the picture of the diamond wasn’t enough to light up their brains.[34][35][36] It’s like their reward systems weren’t catching on that something good was about to happen.

So that’s one big thing that could be different about your brain if you have ADHD. Something else scientists are looking at - has to do with this thing called “executive functioning[37].”

RF It’s like the part of your brain that’s the air traffic controller that tells you what to be focused on and what to ignore[38]. But people with ADHD have a real hard time screening out other extraneous thoughts. They tell me, you know my brain is on 14 different channels. And that’s hard! Imagine trying to get things done with your brain on 14 channels all the time.

If your brain’s running on 14 channels, and your reward system is powered down, it can actually be dangerous. Like, people with ADHD are at higher risk for lots of things. They’re more likely to get into car accidents[39], to go to prison[40], to be suicidal.[41] They’re even more likely to die earlier than someone who doesn't have ADHD.[42][43][44] But drugs like Adderall can help change this[45][46][47][48]. It can help their brain pick a channel, and stay there[49].  

RF If you give somebody a stimulant, so if you have a slightly sluggish reward network, and you give somebody a stimulant and normal things like finishing your homework, finishing your assignment [50], gives you a sense of reward, then it becomes easier to do. What my patients have said to me  over the years that it's like you gave me my brain back, it's my brain but it actually works how it's supposed to!

Overall, studies find that Adderall can make a big difference for people with ADHD[51][52].  Like, one trial of about 400 adults with ADHD found that 65% of them got better on Adderall. That’s compared to 20% on placebo[53]. Tons of other trials also find it can really help people[54][55]. For people who don’t respond well to Adderall, they might do better on other meds like Ritalin[56][57].

So, this all sounds great. But what if it’s a little too good to be true? A lot of people are worried that maybe we’ve gone too far here[58]. After all, in the US, stimulant prescriptions doubled between 2006 and 2016[59]. We couldn’t find an exact number, but it’s estimated that millions of people are prescribed Adderall[60] and remember, this is a drug that’s similar to meth! … After the break, what are the downsides here? Is there a dark side to this drug?

<<BREAK>>

Welcome back. Today, we’re looking at Adderall. We know that it can help with ADHD, but some people are kinda freaked out about the fact that we’re giving amphetamine to millions of people[61], including kids[62][63] Plus, lots of people who don’t have ADHD take Adderall to party or to help them study.  So … should we be worried?

For this, I called up Professor Habibeh Khoshbouei, a neuroscientist at the University of Florida.[64] I asked her how close is Adderall to Meth?

HK: So the similarity between Adderall and methamphetamine is that their basic structural backbone is amphetamine.

RR: They have the same like skeleton.[65] 

HK: Yes, it's the same chemical structure.

Yeah, they’re super similar. They’re both amphetamine. And they work in a similar way: by fiddling with the dopamine in our brains[66] … it’s one of the brain juices that makes us happy[67]. And this happy chemical is really important for our survival ...

HK: When we eat something really good, we have higher dopamine level. We feel good…. And so that's why we don't starve to death and we go seek food because we are wired to seek the reward.[68]

So, you eat an ice-cream cone, bam - little squirt of dopamine comes out. But we don't want that dopamine just hanging around. Because we need the levels to go back down - so they can pop back up the next time something nice happens ... And your brain has a little clean up crew to help with this - it steps in to suck dopamine back up into the neuron.[69]

HK: This vacuum cleaner vacuums it, it cleans it up.

RR: So dopamine is like the dirt?

HK: Yes. It’s cleared it up, vacuum it back, put it in the neuron, stores it and is ready for another release cycle.

Adderall and meth are like special dirt– the vacuum cleaner sucks it up instead of dopamine.[70][71][72] That changes the amount of freewheelin’ dopamine in your brain. These drugs also tweak other brain chemicals, like Nora Ephron. I mean, norepinephrine.[73][74]

So Adderall and meth are similar. But what really matters here - is how the drug gets into your system.

With ADHD, if you're following a doctor’s orders, you're probably swallowing a pill. It has to get broken down, travel through your digestive tract, circulate throughout your bloodstream before it finally starts to get absorbed into your brain. All this means it can take more than an hour for it to start hitting your brain.[75][76] Compare that to smoking[77][78], injecting[79], or snorting a drug like Meth[80]. It gets to the brain much faster.[81] Senior producer Meryl Horn asked Habibeh about this.

HK: When something is injected. The majority of the drug gets to the brain within a few minutes![82] That's why it gets this the feel of rush.

MH: And why- what is the rush, like why does that rush matter?

HK: Oh, the rush.

HK: So that rush is huge. And it's something that like… I actually I never exposed to it. But this is what I read. It's the type of feeling that they never felt before.

If it feels really good, you might start seeking it out above everything else in your life.[83] Which means that if you inject yourself with amphetamine, or crush it up and snort it, it can put you at a bigger risk for addiction than if you take it in a pill.[84][85][86]  

But that doesn’t mean there’s no risk, for people who take this stuff in a pill.[87][88]  So - can people with ADHD get addicted to their meds?  Well, we couldn’t find many studies on this– but the experts we spoke to said the risk for this is really low[89]. They said, sometimes people get confused about the difference between needing the drug to function every day versus being addicted to it. Think about a person with diabetes– they need to take insulin - but no one says they’re addicted to their insulin. Being addicted to something means that it’s screwing up your life[90][91]. For many people with ADHD, taking these meds, improves their lives.

HK I am very very passionate about this, because I understand the stigma of it. But people who need it, it’s really really helpful to them.

Scientists we talked to heard that parents were sometimes worried their kids who take Adderall would eventually seek out stronger drugs. But that doesn't seem to be happening. One study followed kids prescribed stimulants including Adderall into their teenage years, and found, they weren’t more likely to have tried illegal drugs than kids with ADHD who were not medicated[92]. Other studies agree[93]. All this makes some researchers recoil when they hear stuff like “Adderall is f***ing speed.”  

MH: Some of the people out there are saying that, you know, all these people on Adderall, they're really just on speed.

HK No, no, no. Who said that? Yeah, no, no. That's absolutely, absolutely wrong! So the thing is that this is incorrect way of describing the certain population who needs medication. They're not on speed. They are taking their medication.

So it seems like a lot of the hand-wringing about Adderall is just your standard drug paranoia. Still, this doesn’t mean Adderall is all rainbows and butterflies. We actually don’t have long term studies on adults taking Adderall[94]. And we do know it can have side effects in the short term.

Most commonly– lower appetite, higher anxiety, and insomnia[95]. And actually, the insomnia thing– that rings true for Kai. She’s the pug mom and actor we talked to earlier. Adderall worked great for her at first, but after about six months, she realized it was keeping her up at night.

KL So I would have trouble falling asleep but then have a lot of trouble staying asleep. So if I woke up in the middle of the night, I wouldn’t be able to go back to sleep for several hours, if at all. To the point where I unfortunately became kind of a zombie.

One study found that about 10% of ADHD patients on stimulants say they have trouble sleeping[96]. Kai actually ended up switching to Ritalin, a different kind of stimulant, and that’s  been working better for her.

There’s a couple other side effects we should mention.

In kids, we know that taking stimulants can slightly stunt their growth if they take them a long time– by a centimeter or two, on average[97][98]. And in general, it’s pretty typical for someone’s heart rate and pulse to increase a little bit while on stimulants[99][100]. So doctors often won’t give them to people with certain heart conditions[101][102][103].

Bottom line? Not everyone can take these meds. But for those who can– experts pretty much agree, the positives outweigh the negatives here. The American Academy of Pediatrics[104], Canadian Pediatric Society[105], and Britain’s National Health Service[106] all recommend that stimulants be tried in patients with ADHD over age 6. 

But let’s talk about the people who are taking Adderall who DON’T have ADHD. We know you’re out there[107][108]! And we know a lot of college students are taking this stuff to study …

RF Oh my gosh, yes[109][110] 

That’s Rachel Fargason again, who we heard from earlier in the show.

RF: Funny story, I might have a patient who ran out of adderall, I just called my daughter in college she just asked a few of her friends and it’s floating all around

One review found that almost one in five college students admit to taking Adderall that wasn’t prescribed to them[111]. Taking it to study was the main reason why[112][113]. And Rachel wondered what it was doing for them– were they really getting a brain boost from these meds? So she set up an experiment to try to find out. She and her team posted flyers all around her campus asking for volunteers…

RF And you can imagine these were very enthusiastic students, they couldn't wait to be in the study

RR laugh

Rachel’s team ended up with 32 participants. These were people who did not have ADHD.[114] They came into the lab several times. Each time, they took a pill.  Sometimes the pill was Adderall, and sometimes it was a placebo.

RF We tricked them. One time we told them they got Adderall, they did not get Adderall, they got placebo. One time we told them they were getting placebo, they got Adderall.

The students knew going in that they’d be tricked– that they wouldn’t know for sure when they were given Adderall and when they weren’t. After taking the mystery pill, the students took some tests. About two hours of cognitive testing. Memory and attention tests. Stuff like…

RF I might give you a whole bunch of things to remember, ask you in one minute what you remember, 3 minutes, 5 minutes, and 15 minutes what you remember

The goal was to see how the students performed on tests when they were actually on Adderall versus when they thought were on Adderall. And the first thing Rachel found was that they could not tell the difference between the real stuff and the fake stuff.

RF We asked them — what do you think you actually got? They only guessed right 50% of time, which is equivalent to chance. So no, they could not tell if they were on Adderall or not. They thought they knew, they were very confident oh I got it today or I didn't but they could not tell if they were on it or not

Secondly, Rachel looked at how well they did on the tests. She’d given them about 30 little tests each time. When they were on Adderall, she saw a small improvement– they did a bit better on two of them.

RF So did it have some mild improvement? Yeah, little teeny bit, but it would not improve somebody's grades.

Yeah–nothing to write home about. In fact, similar studies have found that you’d get the same result from a strong cup of coffee[115]. OK so this last thing Rachel found is really surprising.  When students believed they got Adderall– regardless of whether they got the drug or not, they did a lot better.

RF And that had a far more robust result than the drug itself. It’s pretty interesting isn't it?

RR yeah!

The expectation that Adderall would give them a boost, DID give them a boost. Students who thought they were on Adderall did better on 6 tests … So for people who DON’T have ADHD - it seems like the placebo effect of Adderall might matter more than the actual Adderall.

This isn’t the only study that found Adderall doesn’t boost test scores for people without ADHD.[116][117][118] One study tried it on people taking practice questions from the SATsand they found no big difference.[119] And when a group of researchers followed non-ADHD students in the real world who take Adderall  to help them study, it turned out their GPAs didn’t improve over time[120].

OK, so if you don’t have ADHD - Adderall probably isn’t going to help you much. And remember when you take this drug you are weighing the upsides versus the downsides– like the side effects we talked about … and the possibility of addiction. Plus - if you’re buying it on the street - you may not know exactly what you’re getting. And there have been cases of fake Adderall pills having stuff like fentanyl in them, which can be really dangerous[121].

All right, big picture, where does this all leave us?

1. Adderall does work for lots of people with ADHD. And it can actually be a really big deal - saving them from car crashes, for example. So for them, this is medicine. And the shortage sucks. We don’t know exactly when it’s gonna be over. Some pharma companies say it should ease up in the next couple of months.[122] 

2. It is similar to meth. But people who have ADHD and take it how they’re supposed to - seem to be at a pretty low risk of getting addicted to it.

And 3 - if you don’t have ADHD, it’s not much of a brain booster. No matter what your chem lab partner says.

That’s Science Vs.

CITATIONS PARTY

Montage of tape from Season 13:

WZ Someone’s in the bathroom! Someone’s in the bathroom! Gah!

MH And we’re going to go to Balls Ford Road. RR Pardon? MH You know, Balls Ford Road. RR I think that’s where Thomas Jefferson uhhhhhhh … MH forded his balls?

JA They looked at testis and there was no sperm! And they were like holy cow!

THB: That's nonsense. That's totally - that's you know, it's it's trying to sell you something. It's trying to sell you something that you don't need.

AE So I put in my citations and I’m like, they’re going to understand me, they’re going to know what I’m saying. And a reviewer said - she put a YOUTUBE LINK as a CITATION?! I was like - I thought you guys were going to love this! Haha

JK We were all in a room together working on things, and we kind of all gather around one person's computer screen to look at images as they came up. Oh, look at that one, oh look at that one.

RR: Um why does its head look like a butt?

JE: Like a butt? [Giggle] So in some pictures you you get that impression, right, don’t you? It's like two cheeks.

RR Yeah haha.

WZ I'm a little overwhelmed. I can't. I just. I just can't believe it that this was a human a month ago.

BT: It's just incredible.

WZ: You can't stop running your fingers through it.

BT: I can't stop running my fingers through it.

By the way, I first heard Kai’s story on a really cool podcast called ADHD Aha! It’s all about stories of people recognizing and dealing with their ADHD. You should check it out.

Also, check out the podcast The Journal. Our colleagues there are rolling out a miniseries on the reckoning at one of those Adderall-dispensing online companies. Dropping soon.

Finally– we talk about addiction in this episode. If you or someone you know is struggling with addiction, in the US you can call the Substance Abuse and Mental Health Services Administration’s National Helpline: 1-800-662-HELP or visit their website.

This episode was produced by me, Rose Rimler, with help from Meryl Horn, Michelle Dang, and Disha Bhagat. We’re edited by Blythe Terrell. Editing help from Caitlin Kenney. Wendy Zukerman is our Executive Producer. Fact checking by Diane Kelly. Mix and sound design by Bumi Hidaka. Music written by Bumi Hidaka, Emma Munger, Bobby Lord, SoWylie, and Peter Leonard. And a big thanks to all the researchers we spoke to including Dr. Kenny Handelman, Prof. Gail Tripp, Prof. Lily Hechtman, Dr. Nora Volkow, Prof. Stephen Faraone, Dr. Zheng Chang, and Prof. Carl Hart. A big thanks to Annette Heist, Anya Schultz, and Thom Dunn. And this is our last episode of the season! So an extra special thanks to everyone who helped us out this season, including Jack Weinstein and Hunter, Chris Suter and Elise, and Presha Bhagat. We’ll see you next year!


[1] The combination of dextroamphetamine and amphetamine (Adderall, Adderall XR, Mydayis) is used as part of a treatment program to control symptoms of attention deficit hyperactivity disorder (ADHD; more difficulty focusing, controlling actions, and remaining still or quiet than other people who are the same age). Adderall is used to treat ADHD in adults and children 3 years of age and older.

[2] CDC: ADHD is one of the most common neurodevelopmental disorders of childhood. It is usually first diagnosed in childhood and often lasts into adulthood. Children with ADHD may have trouble paying attention, controlling impulsive behaviors (may act without thinking about what the result will be), or be overly active.

[3] On October 12, 2022, FDA posted a shortage of the immediate release formulation of amphetamine mixed salts, commonly referred to by the brand name Adderall or Adderall IR…FDA is in frequent communication with all manufacturers of amphetamine mixed salts, and one of those companies, Teva, is experiencing ongoing intermittent manufacturing delays. Other manufacturers continue to produce amphetamine mixed salts, but there is not sufficient supply to continue to meet U.S. market demand through those producers.

[4] FDA drug shortages page: Amphetamine Aspartate; Amphetamine Sulfate; Dextroamphetamine Saccharate; Dextroamphetamine Sulfate TabletS: Currently in Shortage

[5] The National Community Pharmacists Association surveyed store owners and managers about their experiences purchasing brand and generic Adderall between July 25 and Aug. 5. Of the 358 who responded, 64% said that the medicines were on backorder, the group said. 

[6] NBC News 8/26/2022: Teva Pharmaceuticals attributed the delay to a labor shortage on its packaging line that it said has been resolved.

[7] Bloomberg 10/7/2022: The drug has been in short supply since at least August, an issue that started this summer with a labor shortage at Teva, which supplies more Adderall in the US than any other company.

[8] A spokeswoman for Teva told The Times that those delays have been resolved, but that the company is now facing “a surge in demand,” which is the predominant cause for back orders.

[9] WSJ reporting on the prescribing and the crackdown https://www.wsj.com/articles/dea-investigating-adhd-telehealth-provider-done-11663239601; https://www.wsj.com/articles/cerebral-receives-subpoena-from-federal-prosecutors-11651950307?mod=article_inline 

[10]  The net total of the four stimulants doubled from 2006 (24.42) to 2016 (48.18).  

[11] https://www.sciencedirect.com/science/article/pii/S2589537022002541 

[12] From 2014 to 2019, the national annual rate of stimulant dispensing increased

significantly from 5.6 to 6.1 prescriptions per 100 persons. Rates differed by prescription stimulant

type, with increases occurring among both amphetamine-type stimulants and long-acting

stimulants

[13] NYT Oct 13, 2022: The number of Adderall and generic-equivalent prescriptions has been rising in recent years, according to figures from IQVIA, a data analytics company. Total prescriptions rose by about 16 percent, to 41.2 million last year from 35.5 million in 2019. Axios: Chart of IQVIA data 2017-2021

[14] 2018 MMWR - on ADHD medication in general: The percentage of privately insured reproductive-aged women who filled a prescription for an ADHD medication increased 344% from 2003 (0.9%) to 2015 (4.0%). ADHD medication prescriptions increased across all age groups and U.S. geographic regions, and the increase was confined to stimulant medications. The percentage of prescriptions that were mixed amphetamine salts (Adderall) increased from 2003 (44.6%) to 2015 (59.4%).

[15] During pandemic years:

-Trillian Health report:  for patients ages 22-44, patient volumes and Adderall prescriptions increased in 2020 and 2021, compared to pre-pandemic years (Figure 2). The number of patients in this age group with Adderall prescriptions increased 7.4% from Q2 2019 to Q2 2020, followed by a 15.1% increase from Q2 2020 to Q2 2021

-NYT: More specifically, according to data provided to The Times by Express Scripts, a pharmacy benefits manager, prescriptions across three categories of mental health medications — depression, anxiety and A.D.H.D. — have all risen since the pandemic began … Among Americans ages 20 to 44, numbers of A.D.H.D. medications went up 7 percent from 2017 to 2019, but they increased by 16.7 percent from 2019 to 2021. According to IQVIA, just under 77 million prescriptions were written for A.D.H.D. stimulant medications in 2021, nearly six million more than in 2020.

[16] https://twitter.com/Melt_Dem/status/1586391230698557440 

[17] ADDERALL XR contains equal amounts (by weight) of four salts: dextroamphetamine sulfate, amphetamine sulfate, dextroamphetamine saccharate and amphetamine (D,L)aspartate monohydrate. This results in a 3.1:1 mixture of dextro to levo- amphetamine base equivalent.

[18] Stimulants to be discussed in this review include phenethylamines such as ephedrine and cathine ((+)-norpseudoephedrine); amphetamines such as amphetamine and methamphetamine….

[19]  Adderall® is a central nervous system stimulant prescription medicine. It is used for the treatment of

Attention-Deficit Hyperactivity Disorder (ADHD).

[20]Amphetamines are illegal when they are used without a prescription to get high or improve performance. In this case, they are known as street, or recreational drugs, and using them can lead to addiction.

[21] https://nida.nih.gov/publications/drugfacts/cocaine

[22] Amphetamine is strictly prohibited in Japan.

[23] https://www.lakemedelsverket.se/sv/sok-lakemedelsfakta?substName=amphetamine&activeTab=1

[24]CDC: People with ADHD show a persistent pattern of inattention and/or hyperactivity–impulsivity that interferes with functioning or development:

[25] The long-held belief that persistence of childhood disorder into adulthood was rare has been challenged by the remarkably consistent finding that ADHD frequently persists into adulthood and although childhood evidence of ADHD is required for formal diagnosis, it is possible that a variant may have an adult onset.

[26]  Currently, referrals of adults for ADHD are also increasing at a rapid pace; until the 1990s and even to date, this age group has been a markedly underrecognized and underserved segment of the ADHD population.

[27] JAMA:  prevalence increased by only 26.4% (ie, from 2.96% in 2007 to 3.74% in 2016) among children compared with the 123.3% increase observed in adults (ie, 0.43% to 0.96%). 

[28] CDC: The percentage of privately insured reproductive-aged women who filled a prescription for an ADHD medication increased 344% from 2003 (0.9%) to 2015 (4.0%). ADHD medication prescriptions increased across all age groups and U.S. geographic regions, and the increase was confined to stimulant medications.

[29] ADHD is a common neurodevelopmental disorder of childhood and has a worldwide prevalence of around 5% (Polanczyk et al., 2007). Persistence into adulthood – either as a full clinical diagnosis or as a subthreshold condition with residual functional impairment is frequent, and adult ADHD has a worldwide prevalence of 2.8% (Fayyad et al., 2017).

[30] https://www.imdb.com/name/nm7378663/ 

[31] https://www.uab.edu/medicine/psychiatry/faculty/adult-outpatient/fargason-rachel-m-d; http://scholars.uab.edu/display/rfarg 

[32] The final sample included 14 participants in the ADHD group (8 males, 6 females) and 15 participants in the control group (8 males, 7 females). ADHD participants were diagnosed but had not been treated with stimulants (‘stimulant naive’).

[33] A picture of coins was presented as a reward outcome and the participants were told they would receive the equivalent of R$3 for each reward outcome and nothing for the non-reward outcomes

[34] Responses to Reward Anticipation: Within-group analyses revealed increased BOLD responses in right ventral striatum (rVS) and left dorsal striatum (lDS) in the control group during reward anticipation (Cue A delay – Cue B delay) (Figure 2, Table 1). In contrast, consistent with our predictions, there were no statistically significant hemodynamic effects during reward anticipation in the ADHD group. Between- group comparisons (Control – ADHD) indicated significantly greater responses in rVS and lDS in the controls, compared to the ADHD group.

[35] https://pubmed.ncbi.nlm.nih.gov/17996464/ “Adults with ADHD showed decreased activation in the ventral striatum during the anticipation of gain, but increased activation of the orbitofrontal cortex in response to gain outcomes.”

[36] https://pubmed.ncbi.nlm.nih.gov/18718573/ The finding of ventral-striatal hyporesponsiveness during immediate and delayed reward processing in patients with ADHD further strengthens the concept of a diminished neural processing of rewards in ADHD.

[37] https://link.springer.com/chapter/10.1007/978-1-4614-8106-5_7 [Sci-hub]

[38] Executive functions are thinking skills that assist with reasoning, planning, problem solving, and managing one’s life. The brain areas that underlie these skills are interconnected with and influenced by activity in many different brain areas, some of which are associated with emotion and stress.

[39] Compared with individuals without ADHD, male patients with ADHD (adjusted hazard ratio, 1.47; 95% CI, 1.32-1.63) and female patients with ADHD (1.45; 1.24-1.71) had an increased risk of serious transport accidents.

[40] International studies have reported disproportionately higher rates of Attention Deficit Hyperactivity Disorder (ADHD) among youth and adult offenders across police custody, prison, probation and forensic mental health settings, estimated to fall at around 25%  [Sci-hub]

[41]After adjusting for potential confounders, compared with the non-ADHD group, patients with ADHD showed higher overall mortality (adjusted hazard ratio, 1.07; 95% CI, 1.00-1.17) and higher injury-cause mortality from suicide (adjusted hazard ratio, 2.09; 95% CI, 1.62-2.71), unintentional injury (adjusted hazard ratio, 1.30; 95% CI, 1.10-1.52), and homicide (adjusted hazard ratio, 2.00; 95% CI, 1.09-3.68).

[42] https://journals.sagepub.com/doi/abs/10.1177/1087054718816164?journalCode=jada The persistence of ADHD to adulthood was linked to a 12.7-year reduction in ELE."

[43] During follow-up (24·9 million person-years), 5580 cohort members died. The mortality rate per 10 000 person-years was 5·85 among individuals with ADHD compared with 2·21 in those without (corresponding to a fully adjusted MRR of 2·07, 95% CI 1·70–2·50; p<0·0001). Accidents were the most common cause of death. Compared with individuals without ADHD, the fully adjusted MRR for individuals diagnosed with ADHD at ages younger than 6 years was 1·86 (95% CI 0·93–3·27), and it was 1·58 (1·21–2·03) for those aged 6–17 years, and 4·25 (3·05–5·78) for those aged 18 years or older. After exclusion of individuals with oppositional defiant disorder, conduct disorder, and substance use disorder, ADHD remained associated with increased mortality (fully adjusted MRR 1·50, 1·11–1·98), and was higher in girls and women (2·85, 1·56–4·71) than in boys and men (1·27, 0·89–1·76).

[44] After adjusting for potential confounders, compared with the non-ADHD group, patients with ADHD showed higher overall mortality (adjusted hazard ratio, 1.07; 95% CI, 1.00-1.17) and higher injury-cause mortality from suicide (adjusted hazard ratio, 2.09; 95% CI, 1.62-2.71), unintentional injury (adjusted hazard ratio, 1.30; 95% CI, 1.10-1.52), and homicide (adjusted hazard ratio, 2.00; 95% CI, 1.09-3.68).

[45]  [transport accidents] In male patients with ADHD, medication was associated with a 58% risk reduction (hazard ratio, 0.42; 95% CI, 0.23-0.75), but there was no statistically significant association in female patients.

[46] [suicide] among stimulant users, a reduced within patient rate of suicide related events was seen during treatment periods (0.81, 0.70 to 0.94). Among non-stimulant/mixed users, no significantly increased within patient rate of suicide related events during non-stimulant treatment periods was seen (0.96, 0.72 to 1.30).

[47][criminal behavior]  As compared with nonmedication periods, among patients receiving ADHD medication, there was a significant reduction of 32% in the criminality rate for men (adjusted hazard ratio, 0.68; 95% confidence interval [CI], 0.63 to 0.73) and 41% for women (hazard ratio, 0.59; 95% CI, 0.50 to 0.70).

[48] [vehicle accidents] In the within-individual analyses, male patients with ADHD had a 38% (odds ratio, 0.62; 95% CI, 0.56-0.67) lower risk of MVCs in months when receiving ADHD medication compared with months when not receiving medication, and female patients had a 42% (odds ratio, 0.58; 95% CI, 0.53-0.62) lower risk of MVCs in months when receiving ADHD medication.  

[49] Across randomized trials, the most consistent effect of a single dose of stimulants is enhancement during neuropsychological tasks of the activity of the right inferior frontal cortex and insula, which together are involved in attention control and inhibition.

[50] Five of eight studies (Jangmo et al., 2019; Keilow et al., 2018; Lu et al., 2017; Marcus and Durkin, 2011; Barbaresi et al., 2007) found that ADHD medication treatments were associated with significantly higher scores on tests, significant improvements in grade point averages, significantly fewer days absent from school, and significant improvements in reading. Two of these five (Lu et al., 2017; Marcus and Durkin, 2011) showed that, within-individuals, adherence to medication was associated with higher scores on education entrance tests and marginal improvement in grade point averages. Two of the eight (van der Schans et al., 2017; Zoega et al., 2012) studies found that treatment was associated with a decline in testing scores and worse school performance, and another (Currie et al., 2014) found no relationship between treatment and academic outcomes. Only one of these three demonstrated a significant decline in academic outcomes (van der Schans et al., 2017). [Sci-hub]

[51] Taking into account both efficacy and safety, evidence from this meta-analysis supports methylphenidate in children and adolescents, and amphetamines in adults, as preferred first-choice medications for the short-term treatment of ADHD. (See especially Fig 3)

[52] Amphetamines improved the severity of ADHD symptoms, as assessed by clinicians or patients, in the short term but did not improve retention to treatment

[53] Table 2, CGI-I improved at week 6 = 65.2% (Total triple bead MAS) vs. 20.4% (placebo)

[54] Treatment with Adderall at an average oral dose of 54 mg (administered in 2 daily doses) was effective and well tolerated. Drug-specific improvement in ADHD symptoms was highly significant overall (42% decrease on the ADHD Rating Scale, P<.001), and sufficiently robust to be detectable in a parallel groups comparison restricted to the first 3 weeks of the protocol (P<.001). The percentage of subjects who improved (reduction in the ADHD rating scale of ≥30%) was significantly higher with Adderall treatment than with a placebo (70% vs 7%; P = .001).

[55] In this largest adult ADHD stimulant study to date, results indicate that once-daily MAS XR [mixed-amphetamine salts] 20 mg/day, 40 mg/day, and 60 mg/day doses were safe and effective in the treatment of adult ADHD, combined type. Subjects treated with MAS XR had significantly improved symptoms compared with placebo, as determined by the ADHD Rating Scale.

[56] Of 174 patients in the 6 clearest crossover studies, 48 responded better to AMP, 27 to MPH, and at least 72 to both, which is an 87+% overall response rate if both are tried.  [Sci-hub]  

[57] We found a marked therapeutic response for the methylphenidate treatment of ADHD symptoms that exceeded the placebo response (76% vs. 19%). [sci-hub] 

[58] https://www.nytimes.com/2016/10/16/magazine/generation-adderall-addiction.html 

[59] The net total of the four stimulants doubled from 2006 (24.42) to 2016 (48.18).

[60] US 2020 National Survey on Drug Use and Health Table 1.108 - 11.8 million people over 12 used amphetamine products (prescription stimulant) in 2020.  

 NYT Oct 13, 2022: The number of Adderall and generic-equivalent prescriptions has been rising in recent years, according to figures from IQVIA, a data analytics company. Total prescriptions rose by about 16 percent, to 41.2 million last year from 35.5 million in 2019. Axios: Chart of IQVIA data 2017-2021

[61]  US 2020 National Survey on Drug Use and Health Table 1.108 - 11.8 million people over age 12 used amphetamine products (prescription stimulant) in 2020.  

 NYT Oct 13, 2022: The number of Adderall and generic-equivalent prescriptions has been rising in recent years, according to figures from IQVIA, a data analytics company. Total prescriptions rose by about 16 percent, to 41.2 million last year from 35.5 million in 2019. Axios: Chart of IQVIA data 2017-2021

[62] CDC says, for kids over age 6: Medication can help children manage their ADHD symptoms in their everyday life … Stimulants are the best-known and most widely used ADHD medications.

[63] FDA has approved two types of medications—stimulants and non-stimulants—to help reduce the symptoms of ADHD and improve functioning in children as young as age 6…stimulants, which contain various forms of methylphenidate and amphetamine, actually have a calming effect on hyperactive children with ADHD.

[64] https://neuroscience.ufl.edu/profile/khoshbouei-habibeh/ 

[65]Chemical structures: https://pubchem.ncbi.nlm.nih.gov/compound/Amphetamine; https://pubchem.ncbi.nlm.nih.gov/compound/Methamphetamine

[66] Amphetamine (AMPH) exerts its rewarding and reinforcing effects by elevating extracellular dopamine (DA) and prolonging DA receptor signaling in the striatum.

[67] Affective neuroscience research on sensory pleasure has revealed many networks of brain regions and neurotransmitters activated by pleasant events and states (see figures 1 and ​2) Identification of hedonic substrates has been advanced by recognizing that pleasure or “liking” is but one component in the larger composite psychological process of reward, which also involves “wanting” and “learning” components (Smith et al. 2010).

[68] Neurons in the different regions of the brain comprising the reward system communicate using dopamine: For example, dopamine-producing neurons in the brain’s ventral tegmental area communicate with those in a region called the nucleus accumbens in order to process rewards and to motivate behavior. Neurons that release dopamine are activated when we expect to receive a reward.

[69] The dopamine transporter (DAT) controls the spatial and temporal dynamics of dopamine (DA) neurotransmission by driving reuptake of extracellular transmitter into presynaptic neurons.

[70] After almost 50 years of investigation, the original model for AMPH-induced monoamine efflux has evolved from its simplest form of facilitated exchange diffusion to a multifaceted mechanism that requires not only exchange diffusion and channel-like modes of release but also regulation by second messenger systems.

[71] Methamphetamine (METH) is a substrate for the dopamine transporter that increases extracellular dopamine levels by competing with dopamine uptake and increasing reverse transport of dopamine via the transporter.

[72] The dopamine transporter (DAT)3 is a main target for psychostimulants, such as d-amphetamine (AMPH), methamphetamine (METH), cocaine (COC), and methylphenidate (Ritalin®).

[73] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2413312/ "Methamphetamine causes the release of the neurotransmitters dopamine, norepinephrine and serotonin and activates the cardiovascular and central nervous systems"

[74] https://pubmed.ncbi.nlm.nih.gov/11071707/ These results suggest that NE may contribute to the amphetamine-type subjective effects of stimulants in humans.

[75] After oral doses of MPH [methylphenidate], peak brain level of MPH occur between 1 and 2 h after dosing, which is about the same time of peak PK (serum concentration) and peak PD (behavioral) effects of clinical doses.

[76] participants received an opaque capsule … Amphetamine mixed salts (i.e., generic Adderall) and placebo (dextrose) were selected as the study…. See figure 2: “DEQ Feel Drug” and “DEQ feel high” is significantly different starting 90 mins after adderall capsule was taken compared to placebo

[77] One form of methamphetamine, crystal methamphetamine or “ice,” grew in popularity in the 1980s. It comes in crystallized form, as the name implies, and the chunks can be heated and the fumes inhaled, much like crack cocaine.

[78] Methamphetamine can be smoked, snorted, injected or swallowed.

[79] Table 1.96A on p. 357 of this survey from 2015 and 2016 indicates that people do inject methamphetamine

[80] https://nida.nih.gov/publications/drugfacts/methamphetamine 

[81] Sci-hub Ice, which has been described as the drug of the 1990s, is a pure form of (+)methamphetamine hydrochloride; it is more dangerous because of its purity and because it can be inhaled. Taken by this route, the drug causes an effect similar to that from an intravenous dose, and much more intense than that from ingestion. 

[82] https://doi.org/10.1371/journal.pone.0015269 Fig 1 shows that at 2 mins, about 0.005% dose/cc tissue of injected methamphetamine is in the brain, which is more than half of the peak concentration. [sci-hub]

[83] The onset speed of drug-related effects is a critical determinant of the intensity of mood and behavioral effects of a drug [18,19]

[84] Abuse of amphetamines administered intravenously has become a well established and extensive form of drug abuse. The abuse potential of these drugs when taken by the intravenous route is greater than when taken orally and is comparable to that of heroin or cocaine.

[85] there is one clear public  health implication of our findings: efforts need to be made to discourage injection as a  route of administration by amphetamine users. Credible health information needs  to  be disseminated to users through appropri- ate media  and user networks about the increased risks of experiencing acute and chronic health problems, and of developing  dependence symptoms of sufficient severity to prompt users to seek treatment.

[86] These results demonstrate that intranasal administration of d-amphetamine results in a more rapid onset compared to oral dosing, which could be associated with the popularity of intranasal prescription stimulant use and an enhanced potential for abuse.

[87] SAMHSA: Among people aged 12 or older in 2020, 0.3 percent (or 758,000 people) had a prescription stimulant use disorder in the past year

[88] Mechanism: https://pubs.acs.org/doi/full/10.1021/acschemneuro.8b00137 (on abuse of amphetamine and methamphetamine): tolerance and eventually tachyphylaxis to APA and MA occur rapidly, causing the addicts to take increasing amounts or more frequent doses as they chase a diminishing high (an effect that is not possible because of tachyphylaxis).

[89] See Fig 1a “patients misuse of medications or addiction (6.8%)” out of total Among patients with treatment discontinuation (N = 59), from “320 patients” total patients https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-022-04016-9 

[90] ASAM: People with addiction use substances or engage in behaviors that become compulsive and often continue despite harmful consequences.

[91] Addiction is defined as a chronic, relapsing disorder characterized by compulsive drug seeking and use despite adverse consequences

[92] The originally randomized treatment groups did not differ significantly on substance use/SUD by the 8-year follow-up or earlier (mean age = 17 years). Neither medication at follow-up (mostly stimulants) nor cumulative stimulant treatment was associated with adolescent substance use/SUD.

[93] Results suggested comparable outcomes between children with and without medication treatment history for any substance use and abuse or dependence outcome across all substance types. These results provide an important update and suggest that treatment of attention-deficit/hyperactivity disorder with stimulant medication neither protects nor increases the risk of later substance use disorders.

[94] The effectiveness of Adderall® for long-term use has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use Adderall® for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.  

[95] https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/021303s036lbl.pdf

[96] FIg 2 https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-022-04016-9 

[97] Children treated with stimulants may show delays in expected height gains averaging two centimeters over one or two years. These sometimes attenuate over time and often reverse when treatment is stopped (Faraone et al., 2008).

[98] Treatment with stimulants in childhood modestly reduced expected height and weight. Although these effects attenuate over time and some data suggest that ultimate adult growth parameters are not affected, more work is needed to clarify the effects of continuous treatment from childhood to adulthood. Although physicians should monitor height, deficits in height and weight do not appear to be a clinical concern for most children treated with stimulants. (deficits may not differ between methylphenidate and amphetamine)

[99] ADHD medications raise both blood pressure (<5 mm Hg) and heart rate (<7 bpm) (2–5).  

[100] https://pubmed.ncbi.nlm.nih.gov/16344839/ With MAS XR 20-60 mg/day, mean changes in DBP (1.3+/-9.2 mm Hg; P=.042), SBP (2.3+/-12.5 mm Hg; P=.006), and pulse (2.1+/-13.4 bpm; P=.019) were small and not clinically significant.

[101] the possibility that medications used to treat ADHD might adversely affect the risk of CVD has biological plausibility. Many ADHD medications are stimulants with important sympathomimetic effects and can increase heart rate and blood pressure and potentially increase the risk of arrhythmias, especially in susceptible individuals, such as those with preexisting CVD. Indeed, 2 recent studies 5,6 that examined the CVD risk of stimulant use in adults aged 65 years or older highlight particular concern in older individuals. Tadrous et al5 found that prescription stimulant use was associated with an increased risk of a CVD event at 30 days, with a hazard ratio (HR) of 3.0 (95% CI, 1.1-8.7) for ventricular arrhythmias and an HR of 1.6 (95% CI, 1.1-2.1) for stroke or transient ischemic attack.  Latronica et al 6 noted that older adults exposed to amphetamines had an increased risk of CVD events compared with those who did not take amphetamines (odds ratio, 6.16; 95% CI, 4.22-8.99).  

[102] Obtaining a patient and family health history and doing a physical exam focused on cardiovascular disease risk factors (Class I recommendations in the statement) are recommended by the AAP and AHA for assessing patients before treatment with drugs for ADHD. [American Academy of Pediatrics/American Heart Association clarification of statement - May 2008] [sci-hub]

[103] When asked about cardiac screening practices before initiating stimulant treatment for a recent patient, 93% completed a routine H & P, 48% completed an in-depth cardiac H & P, and 15% ordered an ECG. Almost half (46%) reported discussing stimulant-related cardiac risks.

[104]American Academy of Pediatrics clinical practice guide: For elementary and middle school–aged children (age 6 years to the 12th birthday) with ADHD, the PCC should prescribe US Food and Drug Administration (FDA)–approved medications for ADHD, along with PTBM and/or behavioral classroom intervention (preferably both PTBM and behavioral classroom interventions). Educational interventions and individualized instructional supports, including school environment, class placement, instructional placement, and behavioral supports, are a necessary part of any treatment plan …The evidence is particularly strong for stimulant medications

[105] Canadian Paediatric Society: In combination with nonpharmacological interventions, ER stimulants are recommended as first-line therapy for most children and youth with ADHD.

[106] NHS: 1.5.13 Offer medication for children aged 5 years and over and young people only if: their ADHD symptoms are still causing a persistent significant impairment in at least one domain after environmental modifications have been implemented and reviewed , they and their parents and carers have discussed information about ADHD (see recommendation 1.5.4), a baseline assessment has been carried out (see recommendation 1.7.4).

[107] One survey of 15 thousand college students from this year found that 15% of the students who used stimulant meds like Adderall did it to get high.

[108] "Approximately 2% to 31% of college students reported “getting high” as a motivation for NMU" [NMU = non medical use of stimulants]

[109] 1253 college students– “Almost two-thirds (61.8%(wt)) were offered prescription stimulants for nonmedical use by Year 4, and 31.0%(wt) used”  

[110] "The proportion of students taking prescription stimulants who are approached to sell, give or barter their drugs has been reported to be 16% in rural Midwestern schools 78, 23% in a racially diverse sample of secondary school students 79, and 54% in Midwestern college undergraduates 80, 81. Another study found that a disturbing 22% of the Canadian secondary school students who took licit amphetamines either sold or gave away their drugs 82."

[111]  Random-effects meta-analysis found that the rate of stimulant medication misuse among college students was estimated at 17 % (95 % CI [0.13, 0.23], p\.001) [sci-hub]

[112] Review:  Students are misusing primarily for academic reasons…Fifteen studies asked misusing participants about their motives for misuse. All of these studies reported that the most commonly endorsed motives were related to academics.

[113] “Academic motivations were cited by 50%  to 89% of college students who reported NMU and  were the most common motivations in almost every survey” [sci-hub]

[114] Rachel study: https://www.sciencedirect.com/science/article/abs/pii/S0376871617302983 [Sci-hub]

[115] To summarize, our study showed some moderate effects…with caffeine-positive effects on sustained attention. [caffeine dose = 200 mg]

[116] contrary to common belief, Adderall had little impact on neurocognitive performance in healthy college students. 

[117] 2020 systematic review: Although academic and occupational performance enhancement are the most commonly cited motivations, there is little evidence that academic performance is improved by NMU in individuals without attention-deficit/hyperactivity disorder.

[118] 2020 meta-analysis: There were no effects for D-amph. MPH and modafinil show enhancing effects in specific sub-domains of cognition. However, data with these stimulants is far from positive if we consider that effects are small, in experiments that do not accurately reflect their actual use in the wider population. There is a user perception that these drugs are effective cognitive enhancers, but this is not supported by the evidence so far.

[119] The results did not reveal enhancement of any cognitive abilities by MAS for participants in general… see bottom Table 1– SAT [Sci-hub]

[120] College students taking Adderall (non prescription) did not improve their GPAs

[121] The DEA Laboratory has found that, of the fentanyl-laced fake prescription pills analyzed in 2022, six out of ten now contain a potentially lethal dose of fentanyl…Many fake pills are made to look like prescription opioids such as oxycodone (Oxycontin®, Percocet®), hydrocodone (Vicodin®), and alprazolam (Xanax®); or stimulants like amphetamines (Adderall®).

[122] FDA Drug Shortage Website: See in these charts for Teva products “recovery expected October 2022/November 2022/December 2022”

  • Another company on this list SpecGX has “supply constraints through Jan 2023" for their 20mg and 30mg products
  • Couple companies don’t specify  expected recovery- like Epic Pharma just says “backordered” with no estimates for all their products - and Rhodes 5mg is “unavailable” due to “shortage of active ingredient”