The Skinny On Psychostimulants

The Skinny on Psychostimulants

Happy 2021 people! Are you as happy as I am that 2020 is finally in the rearview?! Weirdest. Longest. Year. Ever. 

That actually makes me think of a new and hilarious commercial I just saw for a big online dating site. It starts out with Satan bored out of his mind in hell, and then he gets a text message from the site saying he’s been matched with a girl, and he’s very intrigued. When they meet, it’s obvious that they’re both instantly smitten. Then the starry-eyed girl introduces herself as 2020. They fall in love. And they live happily (?) ever after… apparently in hell. Unless they stay at her place I guess. Anyway, 2020 is over, even though unfortunately, we’re still schlepping some of its covid baggage, but hopefully not for much longer. 

Considering the euphoria surrounding the new year and the stimulation of resolutions, I thought it very fitting that I start with a three part blog series on pharmacological central nervous system stimulants, aka psychostimulants. One of the main compounds in this class of drugs are the amphetamines, and that will be today’s blog topic. 

As psychostimulants go, amphetamines are very strong ones; they are a group of very tightly controlled and well monitored schedule II drugs. Add a little carbon atom, bind some hydrogens to it, and you’ve got a methyl group; and that makes it methamphetamine, which everyone’s heard of. When prescription methamphetamine is (very) illegally altered…tah-dah…you’ve got crystal meth, aka speed, ice, crank, etc. Other examples of psychostimulants include caffeine, nicotine, cocaine, and other prescription compounds that I’ll cover next week. 

Because of their stimulant activity within the central nervous system, prescription amphetamines are used in the treatment of several disorders, including narcolepsy, obesity, binge eating disorders, and very commonly, ADHD, or attention deficit hyperactivity disorder. They can also be used recreationally in certain populations to get high, to stay awake for long periods of time, and/ or to improve focus and study for exams. In fact, it’s those last two that make amphetamines very popular party favors among college students.

Structurally speaking, amphetamines are drugs that are related to catecholamines, which are chemical messengers that help transmit a message or signal across neural synapses in the central nervous system, from the terminal end of a transmitting nerve cell to the receiving end of a target nerve cell. In an over-simplified explanation, when a signal gets to the end of one neuron, catecholamines help the signal jump to the beginning of the next neuron, hence the name “neurotransmitter.” That message is repeated billions upon billions of times, as there are billions upon billions of neurons in the central nervous system. These neural signals activate emotional responses in the amygdala of the brain, such as fear in a “fight or flight” situation. At the same time, catecholamines also have effects on attention and other cognitive brain functions. Examples of catecholamines include the neurotransmitters dopamine, epinephrine, and norepinephrine. Pharmacologically speaking, amphetamines increase levels of the specific neurotransmitters dopamine and norepinephrine in the neural synapses, which helps the message to make the jump from one neuron to the next. In a way of thinking, amphetamines “speed” the transmission of the message by increasing the levels of these neurotransmitters. Amphetamines increase these dopamine and norepinephrine levels through three different mechanisms of action, at least that we know of: 1) they reverse the direction of the transporter pumps that would normally divert dopamine and norepinephrine away, 2) they disrupt cellular vesicles, thereby preventing the storage of excess dopamine and norepinephrine, which frees them up, and 3) they also promote the release of dopamine and norepinephrine at nerve cell terminals, making them readily available in the synaptic cleft. These three mechanisms combined ensure that there are very high concentrations of dopamine and norepinephrine in the synapses of the central nervous system. The “catecholaminergic” (try that one next time you play scrabble) actions of increasing the levels of dopamine and norepinephrine result in the very strong psychostimulant effects that amphetamines produce.

You’ll notice that I keep saying amphetamines, plural. Why? Because like the neurotransmitters dopamine and norepinephrine it effects, amphetamines are chiral molecules; this is a fancy way of saying that in their three dimensional world, they can exist in different forms called enantomers (more scrabble points!) that are mirror images of each other. I know this sounds complicated, but it’s really not. Think of it as “handedness.” Your left and right hands are mirror images of one another: they look similar, except the placement of the fingers and thumbs are mirror images, and they can do pretty much the same things, like hold a fork or a pencil, but the way they do so differs slightly. The same is true of amphetamines. The two enantiomers of amphetamines are usually referred to as dextroamphetamine (also denoted as d-amphetamine) and levoamphetamine (also denoted as l-amphetamine). All prescription amphetamines boil down to four variations of the amphetamine molecule, which have markedly similar, but potentially slightly variable effects: dextroamphetamine, aka dexadrine; lisdexamphetamine, which is a precursor or pro-drug of dextroamphetamine; methamphetamine, aka methamphetamine HCL, which has that methyl group I mentioned before; and mixed amphetamine, which is essentially a mixture of dextroamphetamine and levoamphetamine at a specific ratio. 

Of those four active forms of amphetamines, there are several brand name drugs on the market, some of which have generic forms available. They are all oral formulations that may be immediate-release, which are typically taken twice a day, or extended-release, which are obviously released more slowly and taken once a day. 

Adderall XR (generic available)

Dexedrine (generic available)

Dyanavel XR

Evekeo

ProCentra (generic available)

Vyvanse

Methamphetamine (Desoxyn)

The desired effects of amphetamines include: stimulation (thank you Captain Obvious), increased alertness, cognitive enhancement, euphoria, and mood lift. Amphetamines have been around for a long time and when taken as prescribed, they’re fairly safe, but there are potential negative side effects. These can include insomnia, hyperfocus, GI irritation, headache, anxiety, slight increase in heart rate and blood pressure, and anorexia. There is addiction potential associated with amphetamines, and there is a short and fairly mild associated withdrawal period where one might feel some fatigue, sleep a lot, and experience strange dreams. 

When taken as directed, and by mouth, usually 20mg – 40mg per day, amphetamines are fairly safe. However, when smoked, injected, or snorted, they are decidedly UNsafe; especially in large doses. I’ve seen people take up to 1000mg per day… though not for long. Why? Because they usually end up dead of overdose. What happens if you choose to use amphetamines in large quantities and/ or via routes other than oral? Hallucinations, delusions, psychosis, seizures, cardiovascular collapse/ arrest, stroke… the bottom line is it ain’t pretty, people, so don’t do it. 

Because amphetamines have multiple mechanisms of action and thereby are very strong psychostimulants, I generally restrict their use to adults only, and choose to use another type of psychostimulant in children called methylphenidate. And that will be the topic next week in psychostimulants part 2 of 3. 

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Thank you and be well people!

MGA