In August of 1951, a strange epidemic struck the sleepy little town of Pont-Saint-Esprit in France. Over the course of a single day, hundreds of people lost their minds.

A little boy tried to strangle his grandmother. A man realized he was an airplane then jumped out a window and broke his legs. Another man tried to drown himself to destroy the snakes that were eating him from inside. Within hours, the nearest asylum was overflowing with lunatics — men, women, children, all of them gripped by some strange madness, shrieking, laughing, gibbering, weeping hysterically. They cried that they were being tormented by demons, they were burning alive, their brains had turned to lead, they were sprouting flowers from their stomachs. It wasn’t long before the asylum ran out of straitjackets. Most of the victims eventually recovered their sanity, but not before five people had died.

The culprit behind the bizarre events in Pont-Saint-Esprit was a fungus called ergot that can grow on rye. The fungus produces a highly toxic brew of hallucinogens with very unpleasant effects; the most important of them is called ergotamine. Ergot poisoning is called ergotism, and improvements in agriculture have made it rare in modern times. Back in the Middle Ages when ergotism was more common, however, it was known as St. Anthony’s Fire, and often it was blamed on witchcraft (like anything else medieval priests couldn’t explain).

But the importance of ergot goes far beyond medieval witch trials. For ergotamine can be hydrolyzed or broken down to yield a compound called lysergic acid. And in the late 1930s, Swiss chemist Albert Hofmann chemically modified this compound to make lysergic acid diethylamide or LSD.



Just like the compounds in the ergot fungus, LSD is an extremely potent hallucinogen, but the similarities end there. Unlike ergotamine, it has relatively low toxicity. Moreover, unlike all the other drugs we’ve looked at so far (heroin, meth, coke) it’s non-addictive.

The chemistry of LSD is fascinating and complex. In this post and the next I’ll look at just a few cool facts about LSD: what happens when you put it under a black light and what happens to it inside your body.

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Why do things have color? It seems like a simple question, but it actually turns out to be very complicated. If an object absorbs some frequencies of visible light and reflects/transmits others, it appears colored, because your eyes can tell the difference between various frequencies of visible light. But what is it about the structure of a molecule that makes it absorb visible light?

Colored molecules usually contain one of two specific features. Look at the structures of the six molecules below: eumelanin, a pigment in human skin (more eumelanin = darker skin color); heme, found in hemoglobin(makes blood look red); sodium ferrocyanide, which is yellow; beta-carotene, the pigment that makes carrots orange; cyanidin, a pigment in berries that makes them purple-red; and lutein, which makes egg yolks yellow. Four of them share one thing in common, while the other two are alike in a different way.

The two at the top, sodium ferrocyanide and heme, contain a transition metal ion like iron with other nonmetallic compounds bound to it. This type of molecule is called a coordination complex. All of the others contain networks of alternating single and double bonds. These are called conjugated systems.

Brightly colored organic (carbon-based) compounds typically contain either a metal complex (like heme) or an extensive conjugated system (like cyanidin). Organic molecules that lack these features are usually colorless.

The reasons why this is true have to do with some more complicated chemistry. I want to keep this simple, though, so I’m going to skip all the gory details and just point out a couple things that will bring us back to LSD.

The world of atoms and molecules is a strange one in many ways. When you throw a baseball, you can throw it as hard or as soft as you want, give it any amount of energy you choose. But an atom or a molecule isn’t like that. It can only have certain specific amounts of energy, just like how you can be on the second or the third floor of a building but not on the 2.25th floor — there is no such place. So a photon of visible light will be absorbed by a molecule if and only if the energy that photon has is equal to the difference between the energy level the molecule now occupies (its “ground” state) and another energy level it could occupy (an “excited” state).

Linking alternating single and double bonds in a series creates closely spaced energy levels for electrons in the molecule to occupy, and the more extensive this network of alternating single and double bonds, the more closely spaced the energy levels become. In extensive conjugated systems, the gap between the ground state and other available energy levels matches the energies of photons in the visible light range, and these molecules appear colored, because they absorb some frequencies of visible light. (With light and all other electromagnetic radiation, higher frequency = higher energy.)

What happens to that absorbed energy? Typically it’s lost as heat (random motion of molecules*). Some compounds, however, lose some energy then re-radiate the remaining energy. Since some of the energy was lost, the compound absorbs photons at one frequency and re-emits photons at another lower frequency. Often, for example, these compounds absorb high-frequency UV light then re-emit low frequency visible light. When you put them under a black light they start to glow. In other words, they’re fluorescent.

If you look at the structure of LSD, you’ll see it has a conjugated system. Not a very extensive one — nothing like lutein or cyanidin — but a conjugated system nonetheless:

The conjugated system here isn’t extensive enough for LSD to absorb in the visible range, and so LSD is a colorless compound. But it does absorb pretty well at some lower frequencies in the UV range. And its structure is such that LSD is fluorescent. When you put it under a black light, it glows.

*Technically heat is defined as transfer of energy from one system to another, and this is important in thermodynamics, where heat has a very specific definition. But in everyday English we use heat like “the metal pan is hot”, and that’s the way I’m using it here.

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Imagine for a minute that you’ve been enrolled in an experiment. We’re going to give you a carefully-measured dose of LSD then take blood samples at periodic intervals to see how the concentration in your bloodstream changes over time. What we’ll end up with is a so-called PK curve, a graph displaying concentration as a function of time. The graph below is from a study where human volunteers were injected with 2 micrograms of LSD per kilogram of body weight.

Now this is with LSD injected directly into the bloodstream, so the concentration is at a max at time t=0. If you’re taking LSD on blotter paper, of course, the drug takes longer to reach the bloodstream (it has to get absorbed into your system first), so concentration will rise to reach a peak rather than starting out at max. Either way, however, your liver will gradually convert the LSD into other compounds or metabolize it, and your kidneys will remove both LSD and the metabolites from your bloodstream. So extensively is LSD metabolized that less than 1% of the original compound shows up in your urine in its intact form.

The half-life is the amount of time it takes concentrations to fall by 1/2. Clearly LSD has a much longer half-life than cocaine, which breaks down very rapidly in your system. But its half life is also much shorter than the marijuana-derived compound THC. And it matters because the length of time it hangs around helps determine the length and intensity of the drug’s effects.

To make matters more complicated, LSD is an extraordinarily potent drug. The doses you need are measured in micrograms or millionths of a gram. These are miniscule compared to the doses of most other drugs you take — think aspirin, for example. Even very low doses produce an extraordinary effect. Why?

The shape of the LSD molecule is a good match for the shape of pockets on certain receptor proteins in the brain, so it binds or latches onto those receptors, in much the same way that the shape of a key makes it able to fit into a particular lock. (This, by the way, is how cocaine, meth, heroin etc. all work — they bind to particular proteins in the brain, although different drugs bind to different proteins with different effects.)

Let’s imagine some LSD molecules floating around in solution together with some serotonin receptors. (Serotonin receptors are a particular class of proteins that act as receptors for serotonin, a neurotransmitter in your brain). At any given time, some of the LSD molecules are binding to receptors, and some other LSD molecules that are already bound to receptors are coming unstuck and floating back off into solution. If we give it enough time, we’ll eventually reach an equilibrium where the rate at which LSD molecules are binding equals the rate at which they are coming loose. The tighter LSD binds to the receptor, the less LSD will be left floating around in the solution.

Biochemists often measure how tightly a molecule binds to a receptor in terms of the Kd, the concentration of the molecule you need to bind 1/2 of the receptor binding sites. The smaller the Kd, the more tightly the molecule is binding its receptor. Now LSD can bind a bunch of different receptors, but it only binds to a few of them very tightly. Since the doses of LSD people take are quite small (and thus the drug never reaches very high concentrations in the brain or bloodstream), it must be these few that act as the primary route by which LSD alters your consciousness. The receptors it binds tightly are specific serotonin receptors: 5-HT1a, 5-HT2a, 5-HT2c, etc. (Serotonin is sometimes called 5-HT.)

In the brain, there are only a relatively small number of neurons that produce serotonin — the number is measured in the thousands. Each of these, however, is connected to many thousands of other neurons in different regions of the brain, so screwing around with serotonin receptors can clearly have far-reaching impact. How exactly this causes the bizarre hallucinations you get when you trip out on LSD is not yet fully understood.

For more on the pharmacology of LSD, see http://www.maps.org/research/cluster/psilo-lsd/cns-neuroscience+therapeutics_2008-passie.pdf, which is not behind a paywall.

Torsten Passie1 , John H. Halpern2,3 , Dirk O. Stichtenoth4 , Hinderk M. Emrich1 & Annelie Hintzen1 (2008). The Pharmacology of Lysergic Acid Diethylamide: A Review CNS Neuroscience and Therapeutics DOI: 10.1111/j.1755-5949.2008.00059.x