More on Adderall Abuse

February 26, 2008

Jonah Lehrer has a piece up on The Frontal Cortex pointing to an entry from n+1 on the diversion of prescription Adderall® for non-treatment purposes in college students. There’s also an older piece on Slate which can only be described as a trip report. Adderall is prescribed, you may know, for amelioration of symptoms associated with Attention Deficit / Hyperactivity Disorder (ADHD).
Jonah says:

Adderall is a composite of several different amphetamines, which are digested by the brain at different rates.

while over at n+1 we read:

The drug comes in a gleaming capsule, blue or tangerine colored, and it can be swallowed or sprinkled over cafeteria applesauce. It is made of equal portions of four amphetamines, all of which the body metabolizes at different rates, and which are packaged in tiny rotund beads that dissolve at varied speeds, so the effect is consistent. A 10-milligram capsule lasts about six hours and a 20-milligram capsule doubles the duration.

These statements may give a slightly incorrect impression.

I should note at the outset that the n+1 reference to “tiny rotund beads” in Adderall XR® is a pharmaceutical “formulation” issue. BigPharma works hard on (patented) tablet, capsule and microbead technologies to modulate the absorption of an oral medication. The purpose is to generate the desired pharmacokinetic drug profile, i.e., how much drug is circulating (or, more precisely, occupying the fluid near the relevant brain or other target sites), how much it changes over time, how long therapeutic levels persist, etc. “XR” stand for “extended release” which as far as I know derives from such formulation tech. I’ll not be discussing this to any length.
Getting back to my main point, the blog quotes tend to imply that Adderall® is a mixture of structurally distinct active molecules. As in “amphetamine” itself, methamphetamine, MDMA (3,4-methylenedioxymethamphetamine), MDA, etc, etc. All of which are referred to as “amphetamines” in the sense of a drug class.
Adderall is rather a composite of the two amphetamine isomers (left hand and right hand mirror reflections of the molecule) and various salts. One of the more common drug salts would be HCl (hydrochloride) and if I am not mistaken the most familiar difference in common drug parlance would be the difference between powder cocaine (cocaine HCl) and freebase cocaine (HCl is stripped off). There are additional salt forms of drugs which might be useful because generally the drug is reduced to base in the body prior to being effective. Any change in the speed with which this modification of the administered drug salt takes place would alter the effective pharmacokinetic profile. (Here you may think about why some people would prefer to use freebase cocaine over cocaineHCl…). So what is this Adderall stuff, anyway?
From Wikipedia:

… Adderall XR is composed of the following proportions of active ingredients[1]:
* 1/4 dextroamphetamine saccharate
* 1/4 dextroamphetamine sulfate
* 1/4 (racemic dextro/laevo-amphetamine) aspartate monohydrate
* 1/4 (racemic dextro/laevo-amphetamine) sulfate

[Additional info from and a marketing site (the name “Vyvanse” for Adderall XR was new to me).]
In other words the active molecule is the same, the alleged difference in activity from canonical “amphetamine” (meaning the d isomer and the HCl, generally) coming from somewhat less-usual salts and the inclusion of the l isomer. In obscure proportion, of course.
I have always been skeptical and thought that Adderall was nothing more or less than a patenting scam. How so? Well, d-amphetamine is an old and long storied prescription medication (the Wikipedia entry has some comments on the Benzedrine inhaler) in addition to its use as a sports doping product (Tom Simpson) and illicit recreational and vocational (think truck drivers) drug. Patenting it as a new drug might be tricky. So what does a smart Pharma do? Why package it up in some modern formulation tech and fake up some odd mixture of salts and isomers and call it a day.
The second part of the equation lies in the relatively consistent finding from laboratory studies that l-amphetamine is considerably less-active (potent) than is d-amphetamine and even more importantly does not seem to confer any substantially different effects. Some of this, I will note, is arguing from a dearth of information at this point because this appreciation was established a long time ago. Meaning that more modern research may hardly ever include the l isomer. Also from a comparison across studies where different salts of the same active compound have been used. Again, not a whole lot here but enough to form a general impression of the likely behavioral consequences of different “amphetamine salts”. I will note that this is not an impossible hypothesis the drug company is advancing. For example the d and l isomers of MDMA confer some interestingly different effects, which I keep meaning to discuss. I just don’t see the same situation for l-amphetamine.
The conclusion here is that I find it unlikely that the minor differences in pharmacokinetic effect produced by the mixed salts really trumps the fancy formulation which modulates drug level. Second, I find it somewhat hard to believe that adding a less-potent isomer with minimal evidence of different effect from the more-potent isomer provides some mystical new therapeutic effect.
Man it would be fascinating to see the clinical research data in which they proved that Adderall beat good old d-amphetamine worked up with all the best formulation tricks to produce a similar PK profile, wouldn’t it?
And even more fascinating to understand the animal models that put them on the track of this precise mixture of isomers and salts!
Okay, that’s my gut, semi-informed feeling. Now let the real pharmacologists descend and point to where I’m wrong….

2 Responses to “More on Adderall Abuse”

  1. MattXIV Says:

    The l-enantomer may affect drug decomposition if the enzymes that ultimately end up breaking it down aren’t stereospecific. If the racemic salts get absorbed first (either from the salt or being packaged different), you could potentially tie up half the bonding sites with the less active enantomer for a while. Not to say that the primary aim of such a tweak (pun intended) couldn’t have been to get a new patent, but playing around with inactive enantomers probably can get you some interesting PK effects.


  2. N.B. Says:

    Just as an FYI, Vyvanse isn’t your garden-variety amphetamine–it’s an amphetamine “pro-drug,” lysdexamfetamine, which is dextroamphetamine conjugated to the amino acid lysine. The whole point of this is so that the drug has to be activated in the GI tract/liver and so that you can’t crush and snort the contents of the capsules for a rapid high. It’s intended to reduce the abuse potential as compared to standard amphetamine dosage forms.


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