Cannabis/Psychedelic 2 Larry Minikes Cannabis/Psychedelic 2 Larry Minikes

Structure of LSD and its receptor explains its potency

Artistic representation of LSD (in blue) fitting into a serotonin receptor (the white ribbon). Credit: Bryan Roth

January 26, 2017

Science Daily/Cell Press

Lysergic acid diethylamide -- more commonly known as "LSD" or simply "acid" -- is one of the longest lasting and most potent hallucinogens, but researchers have never understood why LSD's effects linger for 12 hours or more. The key to the drug's psychedelic longevity lies in how it fits into receptors in the brain, as reported in a study appearing January 26 in Cell.

 

"When I was younger, and The Grateful Dead was still around, I would occasionally go to Grateful Dead concerts. A lot of people took LSD and similar drugs during concerts, and it would be interesting to be in the parking lot hearing people wondering when their LSD experience was going to end," says Bryan Roth, a professor of pharmacology at University of North Carolina and a senior co-author on the study. "A lot of people who take the drug are not aware of just how long it lasts."

 

Scientists from Roth's lab at UNC captured crystallography images (images showing how a molecule's atoms are arranged) of an LSD molecule bound to a human serotonin receptor and discovered that the LSD molecule was wedged into the receptor's binding pocket at an angle no one had expected. On top of that, part of the receptor protein had folded in over the LSD like a lid, sealing the drug inside.

 

"Once LSD gets in the receptor, a lid comes over the LSD, so it's basically trapped in the receptor and can't get out," says Roth. "LSD takes a really long time to get on the receptor, and then once it gets on, it doesn't get off," he added.

 

This finding explains why LSD trips last for a full day, even though LSD doses are extremely small -- the average dose is 100 or so micrograms -- and LSD molecules are cleared from the bloodstream in a couple of hours. Given that there has been a tentative resurgence in testing LSD for some medical conditions, understanding the mechanism of its potent and long-lasting actions may help drug developers design more effective psychiatric drugs with fewer side effects, the researchers say.

 

While speculative, the study's results may help researchers think about how LSD micro-dosing could work. About 1 in 10 Americans have taken LSD at some point in their life, but increasingly, people are taking LSD at doses too small to cause hallucinations with the goal of boosting their creativity and countering depression. LSD micro-dosing has never been clinically tested, and many scientists have doubted that taking such small amounts of the drug would have any detectable effect. But when Roth's group exposed live cells in a Petri dish to micro-dose-sized amounts of LSD, those tiny doses of LSD affected the receptors' signaling. It's as yet unknown how this signaling would translate into an effect on a person's mood or perception, although the studies demonstrate LSD's remarkably potent actions on cellular signaling.

 

LSD's ability to fit in and let the receptor's "lid" close over it depends on the specific chemical structures of both the drug and the receptor. When the team exposed cells with mutant receptors that had floppier lids to LSD, the LSD bound more quickly and also exited the receptor much faster. Those short LSD binding events produced very different signaling patterns than the longer binding events.

 

"I think it's important for the pharmaceutical industry to understand that even if you modify just one tiny aspect of any compound, you may affect the way the entire compound sits in the receptor, and that affects the compound's performance," says study first author Daniel Wacker, a postdoctoral fellow at UNC.

 

The researchers stressed that they do not advocate LSD use, as it is an illegal and potentially dangerous drug. However, its potential medical applications, and its enormous impact on pop culture, warrant an understanding of its modes of action and ways in which they can be modified.

 

A separate study on LSD, published January 26 in Current Biology, found that one of the receptors the team tested plays a role in peoples' experience of music while on LSD.

 

This research was supported by the National Institutes of Health, the National Institute of Mental Health, a Terman Faculty Fellowship, and the Michael Hooker Distinguished Chair of Pharmacology.

https://www.sciencedaily.com/releases/2017/01/170126132541.htm

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Cannabis/Psychedelic Larry Minikes Cannabis/Psychedelic Larry Minikes

Mechanism of Hallucinogens' Effects Discovered

February 2, 2007

Science Daily/Cell Press

The brain mechanism underlying the mind-bending effects of hallucinogens such as LSD, mescaline, and psilocybin has been discovered by neuroscientists. They said their discoveries not only shed light on the longtime mystery of how hallucinogens work, but that the findings also offer a pathway to understanding the function of drugs used to treat neuropsychiatric disorders, which are now being used largely without an understanding of their fundamental mechanism.

 

Stuart Sealfon, Jay Gingrich, and colleagues published their findings in the February 1, 2007 issue of the journal Neuron, published by Cell Press.

 

Researchers have long known that hallucinogens activate specific receptors in the brain, called 5-HT2A receptors (2ARs), that are normally triggered by the neurotransmitter serotonin. Neurotransmitters are chemicals that one brain cell launches at receptors on another to trigger a nerve impulse in the receiving cell. However, a fundamental mystery has been why other compounds that activate the same receptors are not hallucinogenic.

 

In their studies, the researchers compared the differences between the effects of LSD and a nonhallucinogenic chemical that also activates 2AR receptors on the mouse neural machinery. Since the animals could not report the kinds of perception-altering effects that humans experience on hallucinogens, the researchers determined hallucinogenic properties by measuring a head twitch response the mice characteristically showed when under hallucinogens but not when under nonhallucinogens.

 

The scientists concentrated their studies on the cortex of the brain, which earlier studies had shown to be the center for action of the hallucinogens. Their analysis revealed that LSD produced genetic, electrophysiological, and internal cellular signaling responses that were distinctively different from those induced by a nonhallucinogenic compound.

 

They also explored whether 2ARs were central to the hallucinogenic effect of LSD by producing mice lacking the receptors, but in which receptor activity could be selectively restored in the cortex. The researchers found that mice without functioning receptors showed no hallucinogenic response to LSD, but restoring the receptors rendered LSD hallucinogenic in the animals.

 

The researchers wrote that "These studies identify the long-elusive neural and signaling mechanisms responsible for the unique effects of hallucinogens."

 

They also concluded that "The strategy we developed to elucidate [hallucinogen] action should be applicable to [central nervous system]-active compounds, with therapeutic potential in other disorders. Thus, our findings may advance the understanding of neuropsychiatric disorders that have specific pharmacological treatments whose mechanisms of action are not fully understood."

https://www.sciencedaily.com/releases/2007/01/070131135536.htm

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