Today is chemistry day at SciAm blogs!!! Fun times. And of course if Sci was going to participate, of course I MUST participate with NEUROchemistry! It's the best kind!

And today, to really mess with your neurochemistry, we're going to talk about LSD. For some of my other posts on neurochemistry, head over to my other blog, where I've got primers on cocaine (and some of the history thereof), amphetamines, Ritalin, the neurotransmitters serotonin and dopamine, as well as some primers of addiction theories like opponent-process theory.

But today it's going to be LSD. This one will BLOW YOUR MIND, man. And not because of the hallucinations, but because, deep down, we really aren't sure what's going on.



Some History

To get into the history of LSD, you have to get into the history of a nasty disease that we tend of think of as belonging to the past: St. Anthony's Fire, or ergotism. The symptoms inflicted entire families and towns, and included mania, psychosis, and hallucinations, as well as seizures, headache, neusea, diarrhea, gangrene, and of course death. Ergotism is caused by am ergot fungus which infects rye plants, and so anyone who subsequently ate the rye got a dose of the fungus. And the fungus has an interesting little chemical in it called ergotamine (it has quite a bit, up to 2% dry mass of the fungus), which is a precursor to the synthetic drug called Lysergic acid diethylamine, aka LSD or acid.

While St. Anthony's Fire was anything but a pleasant experience, LSD, synthesized from ergotamine in 1938 by Albert Hoffman, is not known for problems like nausea (though that is, in fact, a side effect). No, LSD is known for the acid trip, a hallucinogenic and dissociative experience that has inspired parts of the 1960's counterculture and any of the music videos produced by MGMT (among other things).

The Effects.

Effects we usually associate with LSD include: hallucinations. Hallucinations, however, are not the experience that people usually think of (like pink elephants coming suddenly to make merry in your living room). No, the hallucinations produced by LSD are reported to be more like sensory distortion, colors and surfaces move, moving patterns will appear over still surfaces, objects that are already there will change. This is accompanied (often, the individual experience varies a lot) by something called dissociation, which is a feel of distance from the present or world at large. These experiences are not always positive, and depend a lot on the environment in which people take the drug and how they are feeling when they take it. Depending on dose, effects will last 6-14 hours, and begin about 30 min or more after taking the dose. Some describe the experience as life altering, others as terrifying.

LSD is one potent little guy. Normally when we look at dosing for drugs, we talk in units like milligrams per kilogram, or 1/1000 of a gram. That's pretty small, but it's nothing on LSD. LSD is potent enough to be given in the TENS OF MICROGRAMS, 1/100,000 of a gram. That's very, VERY little drug. Luckily, it's an extraordinarily hard drug to overdose on, so people accidentally taking way too much will usually not suffer problems like convulsions, death, etc, though there are a LOT of possible adverse effects, including things like panic attacks, psychosis, flashbacks that can last for years afterward...and uterine contractions. Just to mix it up a little, I guess.

As for the abuse potential of LSD? Well, that's tough to say. Many pharmacologists now describe LSD as a drug that is abused (taken recreationally instead of for clinical purposes) by humans...but not addictive in the classical sense. We cannot get an animal to self-administer LSD by pressing a lever (but you give them cocaine, for example, and you'll see the animal hit that lever 'til Kingdom come). It's very rare to see people come in for addiction treatment of an LSD problem. That said, there is strong social feeling against LSD and other hallucinogens, and though more people are now studying their effects, legalization or acceptance is unlikely to come any time soon.

That's a brief picture of what someone may experience when taking LSD, but that's not what we're interested in here. The question is: HOW does this happen? What occurs in the brain, what is happening to your brain chemistry, to produce these effects?


Strictly speaking, LSD doesn't play directly with the neurochemistry the way drug like methamphetamine, cocaine, or MDMA do. But the key thing about the chemistry of the brain is that the neurotransmitters, drugs, and whatever else, are only as good as the receptors they interact with. Your brain could be swimming in every chemical you've ever imagined, but if there are no receptors for them, nothing is going to happen.

Agonist? Antagonist? Both?

Chemicals can act in different ways at different receptors. When most people think of a chemical or neurotransmitter hitting a receptor, they think of an agonist. An agonist is a chemical which hits a receptor and stimulates it, which may mean many things from opening an ion channel to activating a large cascades of secondary messenger systems. Sometimes, the receptor that is stimulated by the agonist will be in itself stimulatory to the cell it is on, stimulating that cell to pass on a signal. But sometimes that receptor will be inhibitory, shutting down that cell. So an agonist CAN end up inhibiting neuronal activity, and this does happen pretty often (don't worry, it makes total sense if you twist your mind slightly to the right).

Then of course, a drug can act as an antagonist, which means that it binds to the receptor and inhibits that receptors activity. If that receptor normally stimulates cell activity, you've got a normal seeming interaction. But if it, say, normally inhibits activity and does so ALL the time, then the antagonist shutting it down can actually stimulate cell activity. It all depends on what, exactly, that receptor is doing, and the chemical is just the hapless bum that blundered into it.

And then there's a partial agonist. The partial agonist is the kind of effect that, when first year pharmacology students are introduced to it, makes them whimper a little. You see, a partial agonist stimulates a receptor...PARTIALLY. It's good, but it's not as good as a full agonist. Usually, the chemical that inhabit your brain normally are full agonists for the receptors they hit. So when this drug comes along, it mimics that...partially. Not all the way. It won't be AS GOOD, not as effective. And this means that it ALSO prevents further activation of the receptor, because it's glommed on to that receptor already...and isn't letting anyone else on. So it can also act as a partial antagonist by preventing the receptor from being hit by full agonists. This seems pretty simple until you have to be able to tell what's happening by looking at a random curve on a graph like this.

(Source. Is it just less efficacious, or is it a partial agonist? This question will be on the exam...)

LSD and receptors

So now we know how a chemical can act at a receptor. And we know a chemical is only as good as the receptor(s) it hits. So what is LSD doing in there? Well, it's doing a LOT. While we now can make drugs so specific they hit only one subtype of one type of receptor (and many of the drugs you commonly think of hit relatively few receptor types), LSD is...not one of those happy specific drugs. Right now we know for sure that LSD has activity at: dopamine receptors, adrenergic receptors, and serotonin receptors 1A, 2A, 2C, 5C, and 6. Some glutamate receptor activity is also required for the effects of LSD. Heck, there may be more. LSD doesn't like to play nice. I could go down the list and give you a full run down, but today, we're just going to focus on the main receptor thought to mediate the hallucinogenic effects of LSD: The 5-HT2A receptor.

5-HT2A stands for serotonin 2A type receptor, or a receptor for the neurochemical serotonin. We usually think of serotonin in terms of things like mood, but in fact serotonin receptors (remember, a chemical is only as good as its receptor!) are spread all over the body and play roles in drug abuse, mood, gastrointestinal function, migraine, and a whole pile of other functions and disorders. The serotonin system has between 14 and 17 different subtypes of receptors right now (depending on who you ask). 5-HT2A is one of the most well characterized. It's the main stimulatory serotonin receptor (though its actions can be inhibitory depending on where it's located), stimulating activities within the cell like calcium signaling.

You can find 5-HT2A receptors ALL OVER the central nervous system, as well as in the gastrointestinal tract and in your circulatory system. But what we're interested in right now is the brain. 5-HT2A receptors are all over the brain, but we think they are particularly important in the frontal cortex, and possible in the visual cortex. And it appears to mediate the hallucinogenic effects of LSD, with a tight correlation between stimulation at the 5-HT2A receptor and hallucinogenic effects of LSD and other types of drugs. Not only that, if you block the 5-HT2A receptor, you block the hallucinogenic effects.

So now we know that LSD acts at the 5-HT2A receptor. And we know these are all over the brain. We are pretty sure that LSD at the 5-HT2A receptor is a partial agonist, so it does stimulate the receptor, but not as well as straight up serotonin might. But how do we get from there to hallucinations?

What we know right now is that when you stimulate 5-HT2A receptors with LSD, you get an increase in glutamate cell activity in the frontal cortex. 5-HT2A receptors are often on these cells, and stimulation by LSD causes these neurons to fire more than they normally might. However, right now, we have no idea HOW this happens. But right now, scientists think that the effects that the 5-HT2A receptor has on glutamate signaling are the ones responsible for the sense of dissociation, the sensory distortion, and possibly those weird wavy lines.

Is this normal, that people take a drug when we have basically no really idea of what it's doing and its mechanism of action? Oh yeah, completely normal. Look at Prozac,we still aren't sure how that one works. Look at Lithium, the drug we know basically nothing about! LSD is by no means alone. The brain is a mysterious place, where drugs and receptors combine with different signaling pathways in different areas of the brain, all combining with each other to produce the you that walks and talks (and maybe takes LSD). And this is only one of the receptors which LSD hits. So when you think of LSD, don't think of pink elephants. A drug is only as good as its receptor, and those 5-HT2A receptors, they will BLOW YOUR MIND, man.


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