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When he started working with the ergot alkaloids and their active ingredient, lysergic acid, he wanted to develop a new stimulant of the circulatory system. He based his design of LSD-25 on the successful drug Coramine (nicotinic acid diethylamide). Hoffman's first synthesis of lysergic acid diethylamide (LSD)-25 in 1938 yielded nothing of interest in his pharmacological assessment. His curiosity about the chemical structure of the drug led him to make the product again one day in 1943, when he accidentally dosed himself with the synthesized product. Curious to learn more about the "not unpleasant" experience, he repeated the dosing on April 19, 1943 and road his bike home from the lab. Here is a shortened version of his now famous description of his experience:
"The faces of those present appeared like grotesque coloured masks;...a feeling of suffocation; confusion alternating with a clear appreciation of the situation. I lost all control of time: space and time became more and more disorganised and I was overcome with fears that I was going crazy....Occasionally I felt as being outside my body. I thought I had died. My ’ego’ was suspended somewhere in space and I saw my body lying dead on the sofa. I observed and registered clearly that my ’alter ego’ was moving around the room, moaning."Delysid. The timing of Hoffman's discovery coincided with the discovery of serotonin and the birth of neuroscience and the eventual rise of psychopharmacology,leading to a surge in usage of LSD in both psychiatric practice and scientific research in the 1950s and 60s. The rise of hippie culture and concerns about the corruption of youth led to LSD being made illegal in 1967 (the same year as Dragnet's famous Blue Boy episode) and listed as a schedule 1 drug in 1970. As argued here and here, these restrictions have made it difficult for researchers to get the approval to do human studies on LSD and other psychoactive drugs. Thus, they have relied on studies in animals, which have limitations for several reasons, namely that we can't really ask them about their acid trip.
There are several unanswered questions about the neurochemistry of LSD: why are its effects so potent and long lasting?; why does LSD induce hallucinations while other serotonin receptor agonists (activators) don't? To answer this question, researchers solved the structure of LSD bound to its serotonin receptor (5-HT) and measured the rates at which LSD binds and dissociates from the receptor. The results, published in Cell and covered here and here, show that the LSD molecule binds to a pocket in the receptor (5-HT2B), after which the "lid" of the pocket closes itself, which makes it difficult for LSD to disengage. The conclusions from the structure are consistent with their kinetic measurements, which showed very low off rates for LSD from serotonin receptors. When they generated a 5-HT mutant that increased the mobility of the "lid", they found that LSD could bind and dissociate much more quickly. These results help to explain the long-lasting effects of LSD, which can last up to 20 hours even at moderate doses. They also investigated the effects of the binding of LSD on the downstream signaling protein arrestin. They found that when LSD is bound to 5-HT receptors, arrestin can bind more tightly than when LSD is not bound. This is not true for other 5-HT receptor agonists, which may explain the unique effects of LSD.
Two subsequent papers from the Nutt lab explored the brain regions that are involved in these two specific responses to LSD. To understand the basis of LSD-induced ego dissolution, which is defined as the "a compromised sense of possessing an integrated and distinct personality or identity" (exactly what Hoffman described on his bike trip). Their paper, published in Current Biology, used fMRI imaging to look at the connections in the brain in people experiencing this effect. Consistent with the known neuropharmacology of LSD, the images revealed increases in connectivity in areas of the brain high in serotonin receptors. The observed increases in connectivity of the brain correlated with reports of ego dissolution. Interestingly, they also found that LSD increased the connections between sensory systems, creating unusual links between visual cortex, auditory cortex, and senso-motor cortex. These results could explain the occurrence of hallucinations and general feelings of increased senses as well as well as synesthesia (think that sound seems orange or that tastes blue).
|Neuroimaging of the same brain on placebo vs. LSD shows increased connections.|
Hoffman originally intended LSD for a very different purpose and when he tried the drug, he knew its potential for psychiatry and neuroscience. Today, the clinical possibilities of LSD and other hallucinogens remain under explored. A recent retrospective study re-examined work from the 50s and 60s that treated alcoholics with LSD. Using current statistical meta-analyses, they found that alcohol misuse was less frequent after the dose of LSD (59% reported less misuse vs. 38% in placebo-treated controls). One clinical trial showed that psilocybin "magic mushrooms" could help control anxiety; MDMA is currently in clinical trials to help people conquer fear induced by PTSD.
One of my early post on this blog reviewed the book Elephants on Acid and Other Bizarre Experiments. The book includes the titular experiment combining pachyderms and hallucinogens as well as other experiments on LSD. The reason I liked that book was that it highlights how unusual science, which frankly can seem frivolous, can have unexpected applications.