Scientists say they have partly explained what causes the mind-bending effects of hallucinogens—drugs, such as LSD, mescaline, and psilocybin, that trigger states akin to dreaming or madness.

The researchers said their discovery may illuminate more than just the workings of these drugs, which became popular in Western culture in the 1960s though some had been used for millennia.

The findings also offer a path to understanding the function of drugs used to treat brain disorders, sometimes with no clear understanding of how they work, the researchers said.


People on psychedelic drugs, most of which are illegal in most Western countries, sometimes report deep revelations, or experience bizarre patterns or sounds that aren't there. There are artworks designed specifically to enhance these effects if viewed while under the influence. The effects of hallucinogens such as LSD (Lysergic acid diethylamide) can range from pleasant to terrifying. Heavy use may permanently scar the mind.

The scientists, with the Mount Sinai School of Medicine and Columbia University in New York, detailed the findings in the Feb. 1 issue of the research journal Neuron.

Hallucinogens—sometimes taken ritually to induce what users feel are mystical experiences—are known to act on brain molecules called 5-HT2A receptors. These sit on the surfaces of brain cells and act as “keyholes” that can be “unlocked” by one of the signaling chemicals that naturally flow through the brain.

The receptor, normally “unlocked” by the brain chemical serotonin, then causes chemical and electrical changes in the cell, which may consequently relay signals to neighboring cells. This is all part of a complex electrical circuitry that underlies mental activity.

Yet hallucinogens, also called psychedelics, present a puzzle. They “unlock” the same receptors as serotonin, or similar non-hallucinogenic chemicals. So why do they cause such different effects?

The researchers compared differences between the effects of LSD and a non-hallucinogenic chemical that also activates the receptors in mice. Since the rodents couldn’t report the mind-altering experiences that drugged people relate, the researchers gauged these effects by measuring a head twitch the mice characteristically showed when under hallucinogens, but not the other compounds.

The scientists focused on the cortex, an advanced part of the brain in mammals that is responsible for much of thought, perception, memory, advanced motor function, social abilities, language and problem solving. The researchers found that LSD produced an array of electrical and cell signaling responses in the cortex very different from those induced by the nonhallucinogen.

The apparent key to the difference was that LSD activated the receptor in a subtly different way from natural chemicals, said Mount Sinai’s Stuart C. Sealfon, a co-author of the paper. The receptor seems to be “like a switch that can go on in more than one direction,” he explained.

When the mind-bending drug activated the receptor, it not only triggered the typical changes in the cell, it caused additional cell responses, he said. The evidence for this, the group reported, was that the LSD seemed to cause a characteristic chain reaction of brain chemistry involving a class of molecules called G proteins, which are often involved in normal signaling processes.

G proteins can be linked to signaling receptors, such as HT2A. When a signal arrives, the proteins can change the cell in ways that, for example, make either it more or less prone to pass on similar signals in the future. The alterations can last for periods ranging from a few minutes to a lifetime; they’re key to the way our mental world changes over time, for instance with learning and memory formation.

In the experiments, one type of G protein was activated by both non-hallucinogens and hallucinogens; but only the latter also switched on a second type, called Gi/o, Sealfon said.

The significance of the difference is unknown. But it was particularly noticeable in a special layer of cells in the cortex, called Layer 5, Sealfon said. This is often described as the “output” layer of the cortex: it essentially gathers up decisions made in that structure and relays them on to other brain regions, including centers that execute physical movements.

Layer 5 also has extensive interconnections to other parts of the cortex, Sealfon said. It’s also hypothesized to contribute to a certain filtering function, in which it helps squelch unimportant information so that this doesn’t overwhelm other brain areas that don’t need it. Hallucinogens may thus disrupt this filtering, Sealfon speculated. “You have a sensory overload, a less filtered experience of your sensory input.”

ABOUT THE AUTHOR

Science writer Jack Lucentini is founder and editor of the World Science science news webzine. He has worked as a staff writer at three daily newspapers, and as a freelance science writer for a range of publications including The Washington Post, Discover magazine and The Scientist magazine. He earned his bachelor's degree at Oberlin College in Oberlin, Ohio in 1993.