29/01/2021 Know Your Amphetamines - Astral Codex Ten

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Know Your Amphetamines

In the 1950s, a shady outfit called Obetrol Pharmaceuticals made a popular over-
the-counter diet pill called Obetrol...
Jan 25 148 201
In the 1950s, a shady out t called Obetrol Pharmaceuticals made a popular over-the-
counter diet pill called Obetrol. If you're familiar with any of: the 1950s, shady pharma, or
diet pills, your next question will be "did it contain amphetamines?" and the answer is yes,
loads of them. Obetrol was a mix of four di erent amphetamine salts: racemic
amphetamine sulfate, dextroamphetamine sulfate, methamphetamine saccharate, and
methamphetamine hydrochloride. Why did they need four di erent kinds of speed? I'm not
sure. The uncharitable explanation is: for the same reason Dr. Nick's Cure-All Home
Remedy has twelve di erent herbs, ie customers think things with more ingredients are
better.

By the 1970s, people gured out meth was bad, so Obetrol replaced their two
methamphetamine salts with two more kinds of non-methylated amphetamine. But the
FDA continued to crack down, and although the historical paper trail goes kind of dark, it
looks like Obetrol had disappeared by the 1980s.

As usual in pharma, someone bought Obetrol Pharmaceuticals, then someone else bought
them, and a er a few iterations of this, all their intellectual property ended up with a
company called Richwood. They decided to rebrand Obetrol as "Adderall" and pitch it as an
ADHD cure.

Treating ADHD with amphetamines was hardly a new invention. Psychiatrists had been
doing it since the 1930s, albeit with slightly di erent drugs. Remember, many organic
chemicals come in two versions, a "right-handed" or "d" version and a "le -handed" or "l"
version. Benzedrine (a 50-50 d/l split) and Dexedrine (pure d-amphetamine) were the
treatments of choice throughout the mid-20th century. So why was it Adderall - a weird
combination of four di erent salts selected kind of at random by a sketchy diet pill
company - that caught on?

I'm not sure. My best guess is good timing plus good advertising. In the early 20th century,
ADHD was called "minimal brain dysfunction" and diagnosed only in the most extreme
cases. A few children with absolute and total inability to function at all got diagnosed and
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given Benzedrine or Dexedrine; everyone else was le to fend for themselves. As far as I
know, this wasn't because doctors had a principled commitment only to diagnose extreme
cases - I found a paper from 1975 arguing that up to 5 - 10% of children probably had
minimal brain dysfunction, the same number estimated to have ADHD today. Parents just
didn't know about it and didn't really have "take my kid to a psychiatrist" in their set of
plausible options to consider.

In the early 1990s, psychiatric research, a series of popular self-help books, and the business
interests of Richwood Pharmaceuticals all converged on the idea that it was important to
get more people diagnosed with ADHD. Adderall entered the market at exactly the right
time, and it became everyone's go-to ADHD medication.

US Ritalin consumption in millions of doses/year, probably a good proxy for number of ADHD
diagnoses, approximately septupled during the 1990s (source)

Even if we agree that amphetamines are the right treatment for ADHD (many people
don't!), how concerned should we be that the particular amphetamines we use are a random
mix of salts selected by sketchy 1950s diet-pill peddlers? Dexedrine is an older formulation
with pure d-amphetamine (sulfate). No l-amphetamine, no weird combination of salts.
Should we just use that?

This is hard to study, because it's not obvious how to dose both medications. If we start out
suspecting that both isomers are equally strong, we might dose 10 mg of Dexedrine vs. 10
mg of Adderall. But in fact we have reason to think that d-amphetamine is a bit stronger, so
maybe 7 mg of Dexedrine vs. 10 mg of Adderall? But then any di erence we nd might just
be a question of choosing the wrong doses rather than a real distinction.

Arnold, Huestis, and Smeltzer, 1976 and Gross, 1976 compare pure d-amphetamine to a mix
of d and l amphetamines. Both studies nd that both d-amphetamine and l-amphetamine
are e ective stimulants, but that d-amphetamine seems to work better for most people. A

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rat model also nds some modest superiority for d-amphetamine, showing that both
isomers improve attention, but d-amphetamine additionally improves hyperactivity and
impulsivity.

Is there any advantage at all to including l-amphetamine? AHS nd that a small subgroup
of patients seem to do better on it, but this is a study from 1976 and honestly I don't trust
them to nd small subgroups responsibly. And Gross nds that some people have fewer
side e ects on a mix of both than on d-amphetamine alone. This is a bit strange - shouldn't
two chemicals have more side e ects than one chemical? My guess is that d-amphetamine
is just stronger, and so people getting their amphetamines as a mix of a strong chemical and
a weak chemical are e ectively on a lower dose and get fewer side e ects.

James et al switch children back and forth between Adderall and Dexedrine to see which
works best. They nd the winner changes from measure to measure. But the tiebreaker was
just asking the teacher which week the child seemed to be doing the best work in class, and
the teacher chose a Dexedrine week almost twice as o en as an Adderall week.

Joyce, Glaser, and Gerhardt claim to nd that Adderall creates stronger and more prolonged
changes in dopamine release than other amphetamines. But they use a bizarre dosing
regimen which equates 0.5 nmol Dexedrine, 0.68 nmol Adderall, and 1 nmol racemic
amphetamine as "identical doses" of each, based on a theory that l-amphetamine has no
independent action but just modulates d-amphetamine. As far as I can tell this is totally
false, and their study contradicts everything else I know, so I am going to nervously ignore
it for now.

What about the evidence from patient ratings? Online databases contain several thousand
of these...

...and they pretty conclusively show that on average patients prefer Dexedrine to Adderall.
This is unblinded and uncontrolled, we don't know what dose any of them were on, and
patients sometimes like addictive medications that aren't very good for them by normal
medical standards. But again it seems like a pretty resounding victory for Dexedrine, which
is what I'd expect. Honestly it's pretty weird that our go-to ADHD medication includes four

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random salts and a bunch of l-amphetamine when a pure d-amphetamine medication we

could use instead is right there.

I do appreciate Dr. Charles Popper's contribution here; he notes that since Adderall has so
many di erent salts, they take di erent amounts of time to get absorbed by your body,
which means Adderall has a more gradual onset and o set compared to something purer
like Dexedrine. Things with gradual onsets and o sets are probably less addictive and less
likely to produce withdrawals and "crashes". As far as I can tell, this is the strongest pro-
Adderall argument.

Vyvanse is the newest and most expensive member of the amphetamine stimulant family.
It's lisdexamphetamine - ie Dexedrine attached to a random inactive molecule called lysine.
As long as the lysine is attached, it can't stimulate anything. The liver removes the lysine at
a slow, consistent rate, which means that you get a slow, consistent release of stimulant into
the bloodstream. This is advertised as especially good for people who are worried about
addiction. It's hard to abuse or overdose on Vyvanse; no matter how much you take, your
liver will still only activate it at the same, slow rate.

My patients love Vyvanse. I try hard to convince people to take older, less expensive
medications unless they're absolutely sure that the newer ashier one works better, but my
patients are very convinced Vyvanse works better than Adderall. I used to think this was
because something about the complicated timed liver release mechanism makes it
"smoother". This is de nitely what the pharma company that designed it wants me to think,
and I admit there is some evidence for it.

But one neglected perspective is that once you take away the lysine, Vyvanse is basically
Dexedrine, not Adderall. Almost everyone likes Vyvanse better than what they were taking
before. But usually they were taking Adderall before. If Dexedrine is really better than
Adderall - and common sense and the patient rating websites say it is - then that goes some
of the way to explaining Vyvanse's superiority before we even get to the complicated liver
stu . Pharmaceutical companies are always trying to re-release old medications in ways
that bamboozle you into thinking they're new medications, so they can charge more money
for them. In this case they did so good a job that I honestly can't tell if that's what they're
doing or not.

Evekeo takes Adderall's questionable decision to include l-amphetamine and doubles down
on it. Remember, Dexedrine is 100% d-amphetamine and Adderall is 75% d, 25% l. Well,
Evekeo is 50-50. This should make it strictly worse than Adderall, and my patients' feedback
seems to agree with this. The supposed point of making it is those studies that show a small
subgroup of people seem to get some extra bene t from l-amphetamine. The real point of

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making it is probably as a me-too drug; it doesn't require any research, since l-

amphetamine and d-amphetamine have both been around forever, but since it's new and
di erent you can charge a lot of money for it.

I can't think of any situation where it would be reasonable to prescribe Evekeo as a rst-
line stimulant. If someone has done sort of okay on Adderall but has lots of side e ects, and
you put them on Dexedrine and they get worse instead of better, I suppose you could try
putting them on Evekeo to see if they really are in the small subgroup of l-amphetamine
bene ciaries. I'm just annoyed that this relatively rare legitimate use case serves a g leaf
for the inevitable Big Pharma campaign to push this new on-patent very expensive
medication on a bunch of people who don't need it.

Desoxyn is the undisputed king of the patient rating websites. Here's the same graph as
before, except I've added Desoxyn to the last column:

These are some amazing numbers. Adderall itself usually has one of the highest ratings of
the thousands of drugs on the site, Dexedrine beats Adderall handily, and Desoxyn wipes
the oor with Dexedrine (except on WebMD, which has the smallest sample size). This drug
is getting ratings that shouldn't even be possible. And the patient summaries are in line
with this - here are a few:

I have been on every derivative and variation of stimulant, SSNRis SSRI, Tricyclics, beta
blockers and all sorts of combinations of above and never have come across such an
amazing compound. as Desoxyn. I think that there is a de nable di erence in mood
thoughts and the way thoughts ow with memory and with present day crises.

And:

A er dealing with depression and ADD for most of my life, and having tried literally
every conventional anti-depressant and ADD medication, I can honestly and without
hesitation say that Desoxyn is the absolute best medication I've ever used to treat my
ADD.

And:

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How is this not more widely prescribed? My doc had me on Strattera at rst, didn't help
at all. Next I switched to Concerta, which worked, but increased my anxiety, and I had a
crash. Next I switched to Adderall, which had almost the same e ect as Concerta but on
top of that I had no appetite. Finally I switched to Desoxyn and that's when my life
started to turn around. My grades instantly went up and homework became fun for me.
Math problems became like a puzzle, and history became fun, like watching a real-life
movie. Right when I made the switch to Desoxyn, I got caught up on ALL my homework
and my grades instantly switched from D's and F's to B's and A's. Not only that, but my
social anxiety was completely GONE.

All the reviews are like this. And I bet all of these patients are telling the truth. Sometimes I
read drug reviews and I wonder whether these people are special cases, or driven to
exaggerate, but these descriptions match my impression of how the average Desoxyn
patient feels.

What's the catch? Desoxyn is methamphetamine. The FDA and DEA discourage doctors
from prescribing it, but it's still technically legal with an MD's prescription, and there are
still some doctors who will use it for the most refractory cases. It is o cially indicated for
ADHD and obesity (really!), but gets used o -label for narcolepsy and various sleep
disorders.

There's a lot of confusion around the di erence between amphetamine and

methamphetamine. On the one hand you have anti-psychiatry activists who will say that
using Adderall for ADHD is exactly like giving kids crystal meth; on the other you'll have
people who say that obviously normal amphetamine is okay, but meth-amphetamine is a
demonic substance that will hijack your brain and destroy your life. The truth is more
complicated.

Methamphetamine crosses the blood-brain barrier more e ectively than unsubstituted

amphetamine, but I'm not sure how much that matters since people take di erent doses of
both, and a high dose of unsubstituted will end up with more reaching the brain than a low
dose of meth. It seems to inhibit the dopamine transporter more e ectively, which might
matter, but I'm not enough of a pharmacologist to know how much. Meth takes e ect more
quickly, which seems to increase addictiveness in a sort of behaviorist sense where the
sooner a stimulus gets reinforced, the more rewarding it will feel. If all of this sounds kind
of weak to you, you're not alone. Shoblock et al write:

Despite the repeated claims of METH being more addictive or preferred than AMPH,
proven di erences between METH and AMPH in addiction liability and in reward
e cacy have evaded researchers. Animals self-administer METH and AMPH at

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comparable rates (Balster and Schuster 1973) and humans prefer similar doses (Martin et
al. 1971). Also, neither humans nor animals discriminate between equal doses of METH
and AMPH (Huang and Ho 1974; Kuhn et al. 1974; Lamb and Henning eld 1994).
Furthermore, while METH is commonly believed to be a more potent central
psychostimulant than AMPH, no direct comparison on the potency of the two drugs to
stimulate central processes have been veri ed. In addition, no previous study has directly
compared the acute e ects of the two drugs on locomotor activity, an important central
process that contributes tothe de nition of psychostimulant. Moreover, there are no
known neurobiological di erences in action between METH and AMPH that would
account for the putatively greater addictive, rewarding, or psychomotor properties of
METH.

I think there's been a little bit more research since then, but the general takeaway - that the
science doesn't support the vast gulf between these two drugs in the popular imagination -
still seems true.

What's going on? I think addicts use meth very di erently from the way generally
responsible ADHD patients use amphetamine. It's weirdly hard to nd good data on
methamphetamine route of administration, but this study shows that about 60% of users
inject it, 23% snort it, and 52% smoke it - also, see this paper about "the second case of
rectal methamphetamine abuse in the literature". Route of administration makes a really
big di erence in how addictive and dangerous a drug is (see eg crack cocaine vs. regular
cocaine), and I think this is a big part of the di erence between seemingly okay Adderall
users and very-not-okay meth users.

But maybe even bringing up route of administration is getting too complicated. The
simplest explanation of the di erence between meth users and responsible amphetamine
users is that the meth users take much, much more. This study asks abusers how much they
use in an average day, and gets numbers from about 300 to 800 mg. An average clinical dose
of either Adderall or Desoxyn would be about 20 mg a day.

So abusers are taking about 25x a normal dose, and are usually snorting or injecting it. I
think this explains the lion's share of the di erence between "methamphetamine abuse"
and "responsible Adderall use" without having to appeal to chemical di erences between
meth and unsubstituted amphetamines. Those di erences do exist, and they're one reason
why drug abusers prefer the methylated version. They're just not as dramatic as you would
think from seeing a successful college student on Adderall vs. a toothless vagrant on meth.

All of this would seem to suggest that doctors should be less scared of prescribing Desoxyn
- except that if it were true, Desoxyn wouldn't have as big an advantage over Adderall as the

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ratings suggest. I'm not sure what's going on here. Maybe this is just the e ect of the small
but real advantages in BBB penetration and level of dopamine transporter inhibition. Or
maybe it's at least partly placebo - an ADHD patient whose doctor gives them meth feels
like they've been allowed to dabble in forbidden magics, and is properly grateful in a way
that makes them feel like their medication is more e ective. I'm not sure. I only have
secondhand accounts to go on - I'm too much of a wuss to prescribe Desoxyn myself.

When I treat ADHD with amphetamines, I usually start with Adderall/extended release
Adderall, even though realistically Dexedrine would probably be an equally good or better
choice. If it's not working very well or there are too many side e ects, I switch to
Dexedrine/extended release Dexedrine. If Dexedrine doesn't work because it seems too
strong or the patient "crashes" too hard a erwards, or if I'm worried the patient is at risk of
addiction, I will try Vyvanse (or some other solution to stimulant “crashes”); if Dexedrine
works less well than Adderall and I am very confused and the patient is in an experimenting
kind of mood, I might try Evekeo. If none of these work, a braver person than I am might try
Desoxyn. As for me, I give up on amphetamines and start looking at Ritalin, moda nil, or
other options.

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